i  , 


RECENT  ADVANCES  IN 
ORGANIC   CHEMISTRY 


BY  THE  SAME  AUTHOR 

STEREOCHEMISTRY 

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(TEXT-BOOKS    OF    PHYSICAL    CHEMISTRY, 
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RECENT    ADVANCES   IN    PHYSICAL 
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LONGMANS,   GREEN,  AND   CO. 

LONDON,   NEW  YORK,   BOMBAY,   AND  CALCUTTA 


RECENT  ADVANCES  IN 
ORGANIC     CHEMISTRY 


BY 

A.  W.   STEWART,   D.Sc. 

LECTURER   ON  ORGANIC   CHEMISTRY   IN   THE   QUEEN'S   UNIVERSITY,   BELFAST 


WITH  AN  INTRODUCTION  BY 
J.  NORMAN  COLLIE,  PH.D.,  LL.D.,  F.R.S. 

PROFESSOR   OF  ORGANIC  CHEMISTRY   IN    UNIVERSITY 
COLLEGE,    LONDON 


SECOND   EDITION 


LONGMANS,    GREEN,    AND    CO. 

39  PATERNOSTER  ROW,  LONDON 

NEW  YORK,  BOMBAY,  AND  CALCUTTA 

1911 

All  rights  reserved 


TO 

MY   FATHER   AND   MOTHER 


285780 


PREFACE  TO  THE   FIRST   EDITION 

IN  the  present  volume  the  Author  has  aimed  at  giving  a  general 
idea  of  the  researches  which  have  been  carried  out  in  Organic 
Chemistry  within  the  last  ten  years,  but  there  has  been  no  rigid 
adherence  to  this  period  when  it  appeared  desirable  to  include 
earlier  investigations.  A  considerable  portion  of  the  material 
has  not  previously  been  collected  in  volume  form ;  and  as  far  as 
possible  the  most  recent  work  in  each  branch  of  the  subject  has 
been  described. 

Except  in  the  case  of  the  third  *  chapter,  no  attempt  has 
been  made  to  enter  into  stereochemical  questions.  Eeaders 
desiring  information  on  this  subject  are  referred  to  the  Author's 
book  in  Sir  William  Kamsay's  series  of  "Text-Books  of 
Physical  Chemistry." 

In  dealing  with  Organic  Chemistry  two  courses  are  open ; 
for  we  may  consider  the  matter  either  historically  or  from  the 
synthetic  point  of  view.  In  the  present  volume  the  second 
method  has  been  adhered  to  as  far  as  possible ;  and  when  the 
synthesis  of  a  substance  is  known,  its  constitution  has  been 
deduced  from  the  method  of  formation  rather  than  from  its 
decomposition  products.  The  latter,  when  important,  are  re- 
served for  consideration  after  the  constitution  has  been  demon- 
strated. For  the  sake  of  clearness,  each  step  in  the  syntheses 
has  been  treated  in  a  separate  section,  so  that  at  any  moment 
the  reader  can  see  exactly  how  far  he  has  advanced,  and  can 
easily  refer  back  to  any  stage  which  he  may  wish  to  read  again. 

As  no  one  ever  consults  a  book  of  this  type  when  they  wish 
to  know  the  boiling-point  of  a  compound,  it  would  have  been 
superfluous  in  the  following  pages  to  give  more  than  the  most 
general  account  of  the  physical  properties  of  the  substances 
mentioned.  Full  details  on  the  subject  are  to  be  found  in 

*  Chapter  XI.  in  the  present  Edition. 


viii  PREFACE    TO    THE   FIRST  EDITION 

Beilstein's  "  Handbuch  der  organischen  Chemie,"  to  which  the 
reader  is  referred  for  information  on  these  points. 

A  bibliography  of  the  subject  has  been  appended  to  the 
book,  but  it  must  be  understood  that  it  is  not  intended  to  be 
complete;  while  the  same  may  be  said  with  regard  to  the 
references  at  the  foot  of  the  pages.  In  both  cases  the  aim  has 
been  to  furnish  a  guide  to  readers  unacquainted  with  the 
literature  rather  than  to  give  a  complete  list  of  publications. 

For  the  convenience  of  the  reader,  explanatory  footnotes  are 
distinguished  by  asterisks,  while  references  to  the  literature  are 
numbered.  This,  it  is  hoped,  will  obviate  much  unnecessary 
reference  to  the  foot  of  the  pages. 

Some  chapters  on  the  relations  between  chemical  constitu- 
tion and  physical  properties  were  originally  projected ;  but  in 
view  of  the  approaching  publication  of  a  book  on  this  subject 
by  Assistant-Professor  Smiles  in  Sir  William  Eamsay's  series, 
it  seemed  unnecessary  to  go  into  the  matter  in  this  volume. 

In  conclusion,  the  Author  desires  to  thank  Professor  Collie 
for  many  suggestions  made  during  the  writing  of  the  book ;  and 
especially  for  the  Introduction  which  he  has  contributed.  He  is 
much  indebted  also  to  Professor  Inglis  for  improvements  made 
in  the  manuscript  and  for  his  kindness  in  reading  the  proofs  of 
the  work. 

A.  W.  S. 

UNIVERSITY  COLLEGE,  LONDON, 
September,  1908. 


PREFACE  TO  THE  SECOND  EDITION 

SINCE  1908,  when  this  book  was  first  published,  further  re- 
searches have  been  carried  out  in  several  of  the  lines  which 
were  then  dealt  with;  and  consequently  in  this  new  edition 
considerable  modifications  have  been  made  in  order  to  bring 
the  volume  up  to  date.  .The  original  division  of  the  alkaloids 
into  synthetic  and  unsynthesized  types  has  ceased  to  be  useful 
owing  to  the  number  of  these  bodies  which  have  recently  been 
synthetically  prepared ;  and  on  this  account  the  two  chapters 
of  the  first  edition  have  been  fused  into  one.  The  Grignard 
reaction,  though  novel  in  1908,  has  now  become  so  hackneyed 


PREFACE    TO    THE  SECOND   EDITION  ix 

that  there  appears  to  be  no  advantage  in  devoting  a  chapter  to 
it ;  this  subject  has  therefore  been  omitted.  The  same  fate  has 
befallen  the  chapter  dealing  with  the  chemical  action  of  light. 
At  the  time  the  last  edition  was  published,  this  field  of  research 
seemed  to  stand  in  need  of  a  collected  statement  of  the  known 
facts ;  but  at  the  present  time  the  ramifications  of  the  subject 
are  increasing  to  such  an  extent  that  it  is  almost  impossible  to 
weave  the  disconnected  data  into  a  homogeneous  whole ;  and  as 
the  space  which  the  chapter  occupied  was  required  for  other 
questions,  it  seemed  best  to  omit  the  subject  from  this  volume. 
Two  new  chapters,  one  on  the  quinoles,  the  other  on  the 
triphenyl -methyl  problem,  have  been  introduced. 

In  the  present  volume  the  arrangement  of  the  material 
differs  somewhat  from  that  adopted  in  the  first  edition.  Omit- 
ting the  first  and  last  chapters,  the  book  falls  into  two  main 
sections.  The  first  of  these,  Chapters  II.-VIL,  includes  the 
syntheses  a.nd  constitution  determination  of  important  natural 
bodies  and  their  root-substances;  while  the  latter  half  of  the 
book  is  devoted  to  compounds  and  problems  which  have  some 
bearing  on  our  theoretical  views. 

In  the  preparation  of  this  edition  I  have  been  much  indebted 
to  Professor  Inglis,  Assistant-Professor  Smiles,  Messrs.  Austin, 
Clarke,  Crymble,  and  Hilditch. 

I  should  also  like  to  tender  my  thanks  to  my  numerous 
reviewers  both  for  their  criticisms  of  the  previous  edition  and 
for  their  encouragement.  When  writing  the  first  edition,  I 
tried  to  bear  in  mind  that  science  is  not  a  mere  collection  of 
data,  but  is  rather  a  rapidly  changing  series  of  hypotheses  by 
means  of  which  we  attempt  to  group  the  facts  with  which  we 
are  acquainted ;  and  consequently  I  endeavoured  (as  one  of  my 
reviewers  put  it,  more  clearly  than  I  could  do)  "  to  illustrate 
the  principles  upon  which  modern  chemistry  moves  —  not 
stands — and  to  undermine  the  conservatism  which  exists  in  all 
but  strikingly  original  minds."  The  reception  accorded  to  the 
volume  showed  that  this  mode  of  regarding  the  subject  is  more 
general  than  I  had  anticipated. 

A.  W.  S. 

THE  STB  DONALD  CURRIE  LABORATORIES, 

THE  QUEKN'S  UNIVERSITY  OF  BELFAST, 
October,  1910. 


CONTENTS 

PAOK 

INTRODUCTION xiii 

CHAPTER 

I.    MAIN   CURRENTS    IN   ORGANIC   CHEMISTRY  DURING  THE  LAST 

HALF  CENTURY 1 

II.    THE  POLY&ETIIYLENES 20 

III.  THE  MONOCYCLIC  TERPENES 38 

1.  Introductory 38 

2.  The  Synthesis  of  Terpineol 39 

3.  The  Decomposition  Products  of  Terpineol 41 

4.  The  Constitution  of  Dipentene 44 

5.  The  Constitutions  of  Terpinolene  and  Terpinene  ....  50 

6.  Terpin  and  Cineol 52 

7.  The  Synthesis  of  Carvestrene 56 

8.  The  Synthesis  of  Menthone 61 

9.  The  Decompositions  of  Menthone 62 

10.  The  Syntheses  and  Constitutions  of  Menthol  and  Mentherie  63 

11.  The  Constitution  of  Pulegone 67 

12.  The  Constitutions  of  the  Phellandrenes 68 

IV.  THE  DICYCLIC  TERPENES 72 

A.  The  Camphene  Group 72 

1.  Syntheses  of  Camphoric  Acid 72 

2.  The  Synthesis  of  Camphor 75 

3.  Borneol,  Camphene,  and  Camphane 76 

4.  The  Decomposition  Products  of  Camphor .....  78 

5.  Camphoic  and  Apocamphoric  Acids 81 

B.  Fenchone  and  its  Derivatives 82 

1.  The  Constitution  of  Fenchene 82 

2.  The  Constitutions  of  Fenchone  and  Fenchyl  Alcohol  .  83 

C.  Pinene 85 

1.  The  Constitution  of  Pinene 85 

2.  Pinonic  and  Pinic  Acids 88 

D.  Bornylene  and  the  Thujenes 89 


CONTENTS  xi 

CHAPTER  PAGE 

V.    THE  OLEFINIC  TERPENES 91 

A.  Introduction 91 

B.  Isoprene 91 

C.  Citronellal ..    .     i    .....  93 

D.  The  Citral  Group 96 

1.  General 96 

2.  Methyl-heptenone 96 

3.  Geranic  Acid 98 

4.  Rhodinic  Acid,  Rhodinol,  and  Rhodinal 100 

5.  Citral 102 

6.  Geraniol,  Nerol,  and  Linalool 106 

VI.    THE  ALKALOIDS 110 

A.  General 110 

B.  Methods    employed    in    the    Determination    of   Alkaloid 

Constitutions 113 

C.  The  Pyridine  Group 115 

1.  Coniine 115 

2.  Piperine 117 

3.  Trigonelline 119 

D.  The  Pyrrolidine  Group     .    .    • .  120 

1.  Nicotine 120 

2.  Tropidine 124 

3.  Tropine,  ^-Tropine,  and  Tropinone 127 

4.  Tropic  Acid 130 

5.  Atropine 131 

6.  Ecgonine 132 

7.  Cocaine 133 

E.  The  Quinoline  Group 134 

1.  The  Constitution  of  Cinchonine 134 

2.  The  Constitution  of  Quinine 139 

3.  Cinchonidine  and  Conchinine 140 

F.  The  Isoquinoline  Group 140 

1.  The  Constitution  of  Papaverine 140 

2.  The  Synthesis  of  Papaverine 142 

3.  The  Synthesis  of  Laudanosine 145 

4.  Opianic  Acid 146 

5.  The  Constitution  of  Cotarnine 147 

6.  The  Synthesis  of  Cotarnine 151 

7.  The  Synthesis  of  Hydrocotarnine 155 

8.  The  Constitution  of  Narcotine 1 56 

9.  The  Synthesis  of  Gnoscopine  and  Narcotine      .     .     .  157 

10.  The  Synthesis  of  Narceine 157 

11.  The  Synthesis  of  Hydrastinine 158 

12.  The  Constitution  of  Hydrastine 160 


xii  CONTENTS 

CHAPTER  PAGE 

G.  The  Purine  Group 161 

1.  The  Synthesis  of  Uric  Acid 161 

2.  The  Synthesis  of  Theophylline 165 

3.  The  Synthesis  of  Caffeine 166 

4.  The  Synthesis  of  Theobromine 166 

5.  The  Synthesis  of  Purine  .     .     .     .. 167 

VII.    THE  POLYPEPTIDES 169 

VIII       THE   POLYKETIDES   AND   THEIR   DERIVATIVES 178 

IX.    THE  QUINOLES 201 

1.  Introductory 201 

2.  Methods  of  Preparing  Quinoles 205 

3.  The  Properties  of  the  Quinoles      . 209 

4.  The  Constitution  of  the  Quinoles 213 

5.  Intramolecular  Change  in  the  Quinole  Series 215 

6.  Conclusion 221 

X.  THE  TRIPHENYLMETHYL  QUESTION 222 

1.  Introductory 222 

2.  The  Trivalent  Carbon  Hypothesis 225 

3.  The  Hexaphenyl-ethane  Hypothesis 228 

4.  Quinonoid  Hypotheses 231 

5.  Tautomerism  Hypothesis 237 

6.  Conclusion 240 

XI.    ASYMMETRIC   SYNTHESES  AND  NEW  METHODS  OF  PRODUCING 

OPTICALLY  ACTIVE  COMPOUNDS 241 

XII.    SOME  THEORIES  OF  ADDITION  KEACTIONS 253 

XIII.  UNSATURATION 269 

XIV.  CONCLUSION 281 

BIBLIOGRAPHY 290 

NAME  INDEX 297 

SUBJECT  INDEX   .  301 


INTRODUCTION 

AT  the  present  time  it  is  not  altogether  easy  to  say  on  what 
lines  a  text-book  of  Organic  Chemistry  should  be  written.  To 
state  in  the  preface  that  the  Author  "hopes  it  will  supply 
a  long-felt  want"  is  not  always  an  injudicious  method  of 
announcing  the  Author's  belief  in  the  readers  of  text-books. 
For  if  the  "  long-felt  want "  of  the  public  is  to  have  a  restate- 
ment of  all  the  old  facts  once  more,  with  nothing  new,  no  critical 
faculty  shown,  and  an  obvious  lack  of  evidence  that  the  book 
can  be  used  to  broaden  our  outlook  on  other  sciences  as  well  as 
chemistry,  then  no  doubt  the  desire  of  the  public  for  the  time 
being  is  satisfied. 

It  certainly  is  to  be  regretted,  however,  that  so  many  books 
on  Organic  Chemistry  are  published  regardless  of  the  fact  that 
Organic  Chemistry  is  a  growing  science.  If  one  wants  to 
know  about  a  new  piece  of  country,  to  obtain  a  large  number 
of  photographs  all  taken  from  the  same  place  is  obviously 
a  foolish  thing  to  do.  Yet  book  after  book  on  Organic 
Chemistry  is  published,  covering  the  same  ground,  with  a  fine 
disregard  of  the  fact  that  to  the  pioneers  the  outlook  is  con- 
stantly changing.  A  book  that  has  practically  nothing  new 
in  it  except  the  description  of  a  few  more  compounds  is  un- 
necessary. Fortunately,  however,  there  are  some  text-books 
which  are  not  mere  narrations  of  facts,  and  which  do  point  out, 
not  only  what  has  been  done,  but  what  might  be  accomplished, 
and  which  do  make  the  reader  think. 

At  no  time,  moreover,  is  a  change  wanted  in  the  method 
of  writing  text-books  more  than  at  present.  Deluged  as  we 
are  with  unnumbered  facts  that  have  often  neither  explanation 
nor  obvious  connection  with  one  another,  Organic  Chemistry 
has  become  a  vast  rubbish  heap  of  puzzling  and  bewildering 
compounds.  The  sanguine  chemist  expresses  a  hope  that  some 


xiv  INTRODUCTION 

day,  perhaps,  a  few  of  these  may  be  useful.  All  knowledge 
ought  to  be  useful,  even  that  obtained  by  the  manufacture  of 
the  thousands  of  new  substances  which  are  annually  produced 
in  chemical  laboratories.  But  where  is  it  to  stop  ?  When  one 
looks  at  Beilstein's  " Handbook"  or  Eichter's  "Lexicon,"  or 
takes  up  a  current  volume  of  any  chemical  journal,  how  many 
of  the  compounds  or  the  papers  are  of  interest  even  to  the 
most  enthusiastic  chemist?  The  game  of  permutations  and 
combinations  goes  on,  the  chief  object  apparently  being  merely 
to  supplement  the  already  existing  myriads  of  laboratory-made 
organic  compounds. 

How,  out  of  all  this  undigested  mass,  is  the  writer  of  a  text- 
book to  glean  what  is  of  interest  or  tell  what  ought  to  be  taken 
and  what  left?  The  result  is  that  many  text-books  are  not 
much  more  than  abridged  chemical  dictionaries.  The  only  tax 
on  the  reader's  mind  is  to  remember  as  many  facts  as  possible. 
The  text-book  is  rare  that  stimulates  its  reader  to  ask,  Why 
is  this  so  ?  or,  How  does  this  connect  with  what  has  been  read 
elsewhere  ? 

Indeed,  it  is  not  inconceivable  that  a  useful  text-book  might 
be  written  on  the  constitutional  formula  of  a  single  organic 
compound ;  for  instance,  alcohol.  Its  manufacture  and  physical 
properties  would  have  to  be  considered.  This  would  necessitate 
a  knowledge  of  many  typical  organic  compounds,  and  also  of 
many  kinds  of  reactions.  The  evidence  thus  obtained  could 
then  be  summed  up  for  the  purpose  of  expressing  all  these  facts 
by  the  chemical  formula.  Here  the  theory  of  the  constitution 
of  organic  compounds  would  have  to  be  dealt  with,  beginning 
with  the  ideas  in  vogue  at  the  beginning  of  last  century: 
Berzelius'  Electro-chemical  Hypothesis,  of  how  the  nature  of 
the  elements  present  had  the  chief  influence  on  the  properties 
of  the  compound;  Dumas'  Type-theory,  and  how  he  was  the 
first  (about  1840)  definitely  to  recognize  the  arrangement  of 
the  atoms  in  the  molecule :  how  this  idea  took  about  a  quarter 
of  a  century  to  get  into  the  text-books ;  how  Frankland,  in  1852, 
started  the  idea  of  valency,  from  which  sprang  the  modern 
ideas  of  chemical  structure  and  linking  of  atoms ;  how  Kekule 
first  definitely  put  forward  the  idea  of  the  quadrivalence  of 
carbon ;  how  Crum  Brown,  in  1865,  suggested  the  present  form 
of  graphic  formulae  and  pointed  out  that  they  were  "not  to 


INTRODUCTION  xv 

indicate  the  physical  but  merely  the  chemical  position  of  the 
atoms."  All  these  ideas  have  more  or  less  centred  round 
alcohol  and  its  derivatives;  and  any  one  who  carefully  had 
followed  the  reasoning  that  led  to  these  various  mechanical 
methods  for  representing  by  a  chemical  formula  the  molecular 
structure  of  organic  compounds  would  be  in  a  position  easily 
to  recognize  that  our  present  ideas  must  in  future  suffer  change 
just  as  they  have  done  in  the  past. 

Berzelius'  ideas  were  those  of  a  great  mind ;  but  in  his  day 
narrower  theories  were  necessary  for  the  more  detailed  develop- 
ment of  chemistry.  Dumas'  Type-theory,  on  the  other  hand, 
was  too  narrow ;  it  was  a  very  restricted  system  of  classifica- 
tion, and  one  that  led  to  many  false  analogies.  Up  to  the 
present  day,  the  Frankland-Kekule  conceptions  of  valency  and 
graphic  formulae  have  held  their  own,  but  there  are  signs  that 
these,  too,  will  have  to  be  modified ;  physical  as  well  as  chemical 
properties  will  have  to  be  accounted  for. 

The  present  volume  should  be  of  great  use  to  students  of 
organic  chemistry.  The  subject-matter  is  put  in  an  eminently 
lucid  form  that  enables  the  reader  easily  to  follow  all  the 
arguments,  while  at  the  same  time  his  critical  faculty  is 
stimulated.  The  book,  moreover,  is  unlike  so  many  modern 
text-books  in  that  it  is  not  a  mere  compilation  of  facts ;  several 
novel  theories  on  organic  chemistry  are  dealt  with,  theories 
that  up  to  the  present  can  hardly  be  said  to  have  assumed 
definite  shape,  but  which  rather  point  to  the  paths  along  which 
the  pioneers  of  the  science  are  likely  to  go  in  the  immediate 
future. 

J.   NOKMAN  COLLIE. 


CHAPTEE  I 

MAIN  CURRENTS  IN  ORGANIC    CHEMISTRY  DURING   THE  LAST 
HALF  CENTURY 

SPEAKING  exclusively  of  observational  and  experimental  sciences, 
it  is  obvious  that  progress  can  be  accomplished  only  at  the  cost 
of  destroying  or  modifying  current  theories;  for  if  a  theory 
suffices  to  explain  facts  discovered  after  its  promulgation, 
knowledge  may  be  increased;  but  there  is  no  true  progress 
unless  our  general  outlook  is  altered.  Thus  in  science  we  have 
an  alternation  of  two  courses:  in  the  first  the  aim  is  the 
accumulation  of  facts  and  yet  more  facts ;  while  the  second  is 
directed  towards  classifying  these  facts  in  the  most  convenient 
manner.  At  irregular  intervals  some  facts  are  discovered 
which  cannot  be  fitted  into  the  accepted  scheme  of  arrange- 
ment, and  in  order  to  make  room  for  them  the  scheme  has 
to  be  altered  and  recast  into  some  new  form. 

In  every  science  which  is  at  all  progressive  there  must 
arise  from  time  to  time  conflicts  between  the  older  generation 
of  workers  and  the  leaders  of  the  new ;  for,  to  those  who  have 
grown  up  along  with  it,  a  theory  generally  becomes  invested 
with  a  sort  of  sanctity  which  is  quite  out  of  keeping  with 
its  true  make-shift  character.  The  longer  a  theory  stands 
the  harder  does  it  become  to  shake  it,  and  the  greater  is  the 
tendency  of  the  science  to  become  stereotyped.  There  is 
another  side  to  the  question.  Without  any  disrespect,  it  may 
be  said  that  the  majority  of  scientific  investigators  are  not 
possessed  of  strikingly  original  minds— we  cannot  all  be 
Pasteurs — and  hence  there  is  a  very  pronounced  tendency  to 
take  things  as  they  are  and  work  along  the  beaten  track  rather 
than  to  push  out  in  the  wilderness  and  risk  the  chance  of 
losing  the  road  altogether.  Thus  round  every  theory  there 
grows  up  a  little  band  of  workers,  whose  one  aim  seems  to 

B 


3   • -R.ECEm":  ADVANCES  IN  ORGANIC  CHEMISTRY 

be  to  accumulate  evidence  confirming  their  favourite  hypo- 
thesis ;  and  in  this  way  the  theory  gains  a  considerable  weight 
of  supporting  data.  On  the  other  hand,  the  solitary  worker 
who  happens  to  differ  from  the  majority  of  his  fellows  has 
to  overcome  a  tremendous  weight  of  unconscious  prejudice 
before  he  is  able  to  obtain  even  the  semblance  of  an  impartial 
hearing.  In  spite  of  these  difficulties,  however,  progress  is 
made. 

Chemistry  has  proved  no  exception  to  the  general  rule. 
From  the  time  of  the  phlogiston  theory  to  the  recent  work 
of  Kamsay  upon  radium,  the  subject  has  been  intermittently 
developing,  older  theories  have  been  reluctantly  abandoned, 
and  a  gradual  change  of  standpoint  can  be  traced,  each  advance 
being  forced  upon  the  chemist  by  the  impossibility  of  bringing 
new  facts  into  line  with  the  older  views. 

When  we  examine  the  history  of  the  origin  and  growth  of 
scientific  theories  it  is  curious  to  note  how  certain  ideas  seem 
to  pervade  men's  minds  at  a  given  period,  though  they  may 
remain  unformulated  for  some  years  to  come.  Again  and 
again  it  has  been  found  that  two  investigators  have  indepen- 
dently pursued  the  same  line  of  thought,  and  even  accumulated 
vast  stores  of  facts  with  regard  to  the  same  subject,  before  any 
suggestion  has  been  put  forward  publicly.  When  we  examine 
these  cases  more  closely  we  are  often  able  to  trace  the  evolu- 
tion of  the  idea  far  further  back  than  seemed  possible  at  the 
time ;  the  independent  investigators  themselves  may  have  been 
unaware  of  the  existence  of  previous  suggestions  which  bore 
upon  their  views,  but  one  can  hardly  avoid  the  view  that 
at  given  periods  certain  ideas  are  "in  the  air,"  having  been 
carried  so  far  by  previous  workers  that  the  new  view  forces 
itself  upon  several  minds  simultaneously. 

Such  a  crisis  occurred  in  organic  chemistry  almost  half 
a  century  ago,  when  the  foundations  of  our  modern  structural 
theory  were  laid.  Up  to  that  time  the  theory  of  types  had 
served  as  a  stop-gap,  but  it  was  too  clumsy  and  inflexible  to 
respond  to  the  ever-growing  needs  of  a  rapidly  developing 
science.  Only  those  who  have  had  occasion  to  refer  frequently 
to  papers  written  previous  to  1860,  and  who  have  been  forced 
to  transliterate  the  older  formulas  into  those  employed  at  the 
present  day,  can  have  any  idea  of  the  tremendous  change 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY  3 

brought  about  by  the  work  of  Frankland,1  Couper,2  and 
Kekule.3  It  is  not  necessary  to  enter  into  any  discussion  of 
the  part  played  by  each  of  these  in  the  growth  of  the  modern 
structure  chemistry ;  all  three  contributed  an  important  share 
to  the  theory  upon  which  our  work  for  the  last  fifty  years  has 
been  based.  We  may  commence  our  present  survey  with  the 
period  immediately  preceding  the  publication  of  Kekule's  first 
paper  on  benzene. 

Though  the  formulae  of  Couper  and  Kekule  proved  most 
powerful  weapons  in  the  hands  of  those  chemists  who  were 
engaged  in  investigations  of  aliphatic  substances,  the  equally 
important  class  of  aromatic  bodies  still  remained  in  a  state  of 
confusion  equal  to  that  which  prevailed  under  the  type  theory. 
It  was  the  farsightedness  of  Kekule  which  brought  this  to  an 
end  within  less  than  a  decade  by  a  further  advance  along 
structural  lines.  In  1865  he  published  a  paper  on  this 
subject ; 4  and  a  year  later  the  whole  problem  was  thoroughly 
examined  by  him  in  a  treatise5  which  is  probably  as  fine  a 
piece  of  reasoning  as  has  yet  been  devoted  to  a  chemical 
question. 

Kekule  took  as  his  first  premise  the  fact  that  every  aromatic 
compound  contains  at  least  six  carbon  atoms ;  secondly,  when 
a  compound  contains  more  than  six  carbon  atoms  it  is  often 
possible  to  break  it  down  into  one  containing  six  carbon  atoms, 
and  further  decomposition  is  resisted  at  this  point,  which  appears 
thus  sharply  to  mark  a  definite  stage  in  the  process.  From 
these  two  points  he  was  led  to  imagine  that  there  was  some- 
thing in  the  arrangement  of  these  six  carbon  atoms  which 
differentiated  them  from  six  carbon  atoms  grouped  as  in  an 
aliphatic  substance.  Another  step  completed  the  new  theory. 
Having  advanced  so  far,  Kekule  had  but  to  ask  himself  in  what 
way  one  could  arrange  six  atoms  so  that  they  would  not  form 
an  open  chain ;  and  it  is  now  obvious  to  us  that  the  simplest 
reply  is,  in  a  ring.  To  us  to-day,  this  seems  such  a  self-evident 
solution  that  we  are  apt  to  overlook  the  greatness  of  the 
discoverer  and  to  imagine  that  "  any  fool  could  have  done  it." 

Frankland,  Phil.  Trans.,  1852,  142,  417. 
Couper,  Phil  Mag.,  1858,  IV.  16,  104. 
Kekule,  Annalen,  1858,  106,  129. 
Kekule',  Bull.  soc.  chim.,  1868,  1,  98. 
Kekule',  Annakn,  1866,  137,  129. 


4       RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

There  is  a  certain  element  of  truth  in  this,  for  it  is  apparent 
that  such  a  discovery  might  quite  well  have  been  the  result  of 
a  chance  idea;  in  fact,  Kekule  himself  uses  language  which 
might  give  colour  to  this  view,  though  probably  he  did  not 
intend  to  convey  that  impression.  But  Kekule  was  not  content 
with  a  mere  statement  of  the  problem's  solution ;  he  was  able 
to  forecast  at  once  the  line  of  research  which  would  have  to  be 
followed  if  the  theory  were  to  be  put  to  the  test  of  experience. 

First,  however,  Kekule  had  to  explain  how  the  six  carbon 
atoms  in  the  benzene  ring  could  be  linked  together  and  united 
with  the  six  hydrogen  atoms  which  are  needed  to  make  up  the 
complete  benzene  molecule.  One  of  his  early  views  was 
speedily  found  to  be  untenable,  as  it  presupposed  two  sets  of 
hydrogen  atoms— three  and  three,  so  placed  that  a  mono- 
substituted  benzene  derivative  might  occur  in  two  isomeric 
forms.  In  its  final  form,  the  benzene  ring  was  written  practi- 
cally as  we  write  it  now,  with  a  double  bond  between  every 
alternate  pair  of  carbon  atoms  and  single  bonds  between  the 
other  pairs. 

At  the  time  the  benzene  theory  was  developed,  however,  the 
data  which  had  been  accumulated  with  regard  to  aromatic 
compounds  were  not  sufficiently  numerous  to  establish  definitely 
its  truth  or  error.  But  the  new  view  imparted  such  a  stimulus 
to  the  investigators  of  that  period  that  in  a  very  short  time  it 
was  shown  beyond  a  doubt  that  the  Kekule  theory  was  capable 
of  furnishing  an  interpretation  of  all  the  facts  which  had 
previously  been  incapable  of  any  clear  arrangement. 

No  sooner  had  the  benzene  formula  proved  its  value  in  this 
way  than  a  new  problem  was  mooted.  Given  the  benzene  ring, 
it  is  obvious,  as  Kekule  himself  pointed  out  in  his  paper  already 
referred  to,  that  there  must  be  a  certain  fixed  number  of  isomers 
for  each  substituted  benzene  derivative.  For  instance,  if  the 
substituent  introduced  is  always  the  same,  there  will  be  one 
mono-substitution  product,  three  di-substitution  products,  three 
tri-  substitution  products,  and  so  forth.  The  question  then  at 
issue  was  the  possibility  of  determining  the  constitution  of  any 
given  isomer ;  or,  in  other  words,  if  a  poly-substituted  benzene 
derivative  were  produced  in  any  reaction,  what  means  must  be 
employed  to  discover  the  order  in  which  the  hydrogen  atoms 
and  substituents  lay  round  the  ring  ? 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY          5 

The  investigator  who  contributed  most  to  the  development 
of  this  section  of  the  subject  was  Kekule's  pupil,  Korner.  If 
we  take  a  di-derivative  of  benzene  and  introduce  into  the  ring 
one  additional  substituent  (thus  forming  a  tri-derivative)  it  will 
be  found  that  the  number  of  possible  tri-derivatives  depends 
upon  the  constitution  of  the  di-derivatives  from  which  the 
start  was  made.  As  can  be  seen  from  the  figures  below,  an 
ortho  di-derivative  will  yield  two  tri-derivatives,  a  meta 
di-derivative  gives  three  tri-derivatives,  while  from  a  para- 
compound  only  one  tri-derivative  is  formed.  The  relations 
of  the  tri-derivatives  among  themselves  can  be  established  by 
an  analogous  method — 


X 


X 


Korner,  Griess,  Ladenburg,  Graebe,  and  Baeyer  all  aided  to 
establish  the  relations  between  the  various  substitution  products 
of  benzene,  and  in  a  comparatively  short  space  the  filiation 
between  all  the  various  classes  of  benzene  derivatives  had  been 
made  clear. 

It  is  a  curious  study  to  see  how  far  one  can  trace  in  the 
early  controversies  on  the  constitution  of  benzene  the  germs 
of  other  theories  which  came  later  to  their  full  development. 
We  may  take  one  instance  now.  Ladenburg  l  was  the  first 
to  point  out  that  while  ortho-di-substituted  benzene  derivatives 
occurred  in  one  form  only,  the  Kekule  hexagonal  formula 
permitted  two,  which  can  be  expressed  by  the  formulae  below. 

1  Ladenburg,  Ber.,  1869,  2,  140. 


6        RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

Iii  the  one  case  the  carbon  atoms  carrying  the  substituents  are 
joined  by  a  double,  in  the  other  case  by  a  single,  bond — 

CH  CH 

HC    CX      HO    CX 

II     I         I     II 
HC    CX      HC    CX 

\/   v 

Ladenburg  adduced  the  supposed  parallel  case  of  crotonic 
and  vinyl-acetic  acids,  which  differ  in  the  position  of  the  double 
bond  with  reference  to  the  carboxyl  group — 

CH3— CH:CH— COOH  Crotonic  acid. 
CH2:CH— CH2— COOH  Vinyl-acetic  acid. 

He  alleged  that  if  the  shift  of  a  linkage  made  no  change  in 
benzene,  it  should  be  equally  without  effect  in  the  case  of  these 
two  substances.  But  as  they  actually  existed  in  isomeric  forms, 
the  same  was  to  be  expected  in  benzene,  if  the  Kekule  theory 
were  correct. 

Ladenburg  was  responded  to  by  Kekule,1  and  also  by  Victor 
Meyer.2  The  latter  pointed  out  that  while  in  benzene  the 
only  difference  between  the  two  supposed  isomeric  forms  was 
produced  by  a  mere  change  in  the  grouping  of  linkages,  the  case 
of  the  two  acids  shown  above  was  further  complicated  by  the 
fact  that  a  hydrogen  atom  has  also  shifted  its  position  from  the 
end  of  the  chain  to  the  carbon  atom  next  the  carboxyl  group. 
Thus  the  two  cases  are  not  really  analogous  at  all. 

Kekule  attacked  the  Ladenburg  view  from  a  different  stand- 
point, and  we  cannot  do  better  than  quote  his  own  expression 
of  the  case — 

"  The  atoms  in  the  systems  which  we  call  molecules  must  be  considered 
to  be  continually  in  motion.  This  view  lias  often  been  expressed  by  phys- 
icists and  chemists,  and  I  have  already  discussed  it  in  my  handbook. 
Hitherto  no  explanation  as  to  the  form  of  this  intramolecular  motion  has  been 
given,  as  far  as  I  know.  Chemistry  must,  at  all  events,  bring  forward  the 
claim  that  such  a  mechanical  hypothesis  accounts  for  the  law  of  the  linking 
of  atoms.  A  planetary  motion  seems,  therefore,  not  inadmissible  ;  the  move- 
ment must  be  of  such  a  kind  that  all  the  atoms  forming  the  system  retain 

1  Kekule,  Annalen,  1872,  162,  87. 

2  V.  Meyer,  Annalen,  1870,  156,  265  ;  1871,  159,24. 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY          ^ 

the  same  relative  arrangement — in  other  words,  that  they  return  to  a  mean 
position  of  equilibrium.  If  we  now  select  from  the  numerous  conceptions 
which  may  be  formed,  that  which  gives  the  most  complete  account  of  the 
chemical  claims  and  which  coincides  most  closely  with  the  hypothesis  of 
modern  physicists  as  to  the  mode  of  the  motion  of  molecules,  the  following 
assumption  will  appear  the  most  probable. 

"  The  simple  atoms  of  the  system  approach  each  other  in  what  may  be 
considered  a  straight  line,  and  rebound  like  elastic  bodies.  What  we  call 
valency  would  then  have  a  mechanical  meaning.  Valency  is  the  number  of 
contacts  experienced  by  one  atom  on  the  part  of  other  atoms  in  unit  time. 
In  the  same  time  that  the  monad  atoms  of  a  diatomic  molecule  strike  each 
other  once,  the  dyad  atoms  of  a  diatomic  molecule  come  twice  into  contact 
with  each  other,  the  temperature  being  the  same  in  both  cases.  In  a  mole- 
cule made  up  of  one  dyad  and  two  monads  the  number  of  contacts,  under  the 
same  conditions,  in  unit  time  is  two  for  the  dyad  and  one  for  each  monad 
atom. 

"  If  two  atoms  of  tetrad  carbon  are  linked  together  by  one  combining 
unit  of  each,  they  strike  together  once  in  unit  time,  or  in  the  same  time  that 
a  monad  hydrogen  atom  makes  a  complete  vibration.  During  this  time  they 
encounter  three  other  atoms.  Carbon  atoms,  which  we  call  doubly  linked, 
come  in  contact  twice  in  unit  time,  and  further  in  the  same  period  collide 
twice  with  other  atoms. 

"  If  we  now  apply  these  views  to  benzene,  the  formula  which  I  have  pro- 
posed appears  as  an  expression  of  the  following  conception.  Each  carbon 
atom  strikes  against  two  others  in  unit  time,  once  against  one  and  twice 
against  the  other.  In  the  same  unit  of  time  it  comes  once  into  contact 
with  hydrogen  and  completes  one  vibration. 

"  If  we  now  represent  benzene  by  the  hexagon  formula  and  fix  our  atten- 
tion on  one  of  the  carbon  atoms  (that  marked  1,  for  instance) — 

(2)     (3) 
HG— CH 

</        \ 
(1)  HC  CH  (4) 

HC=CH 
(6)     (5) 

we  can  express  the  contacts  it  experiences  during  the  first  unit  of  time  by— 

(I.)  2,  6,  h,  2, 

where  h  stands  for  the  hydrogen  atom.  In  the  second  unit  of  time  that 
carbon  atom  which  has  just  encountered  No.  2  turns  next  to  No.  6.  Its 
collisions  during  the  second  unit  of  time  are — 

(II.)  6,  2,  A,  6. 

While  the  contacts  during  the  first  unit  of  time  are  represented  by  the 
hexagonal  arrangement  above,  those  during  the  second  unit  of  time  are 
represented  by — 


8        RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

(2)     (3) 
HC=CH 

(1)  HC  CH  (4) 

\      / 
HC— CH 

(6)     (5) 

The  same  carbon  atom,  therefore,  is  during  the  first  unit  of  time  doubly 
linked  to  one  of  the  adjoining  carbon  atoms,  while  during  the  second  unit  of 
time  it  is  in  double  linkage  with  the  other  carbon  atom. 

"The  most  simple  mean  of  all  the  contacts  of  one  carbon  atom  is  found 
from  the  sum  of  the  contacts  during  the  first  two  units  of  time,  which  then 
repeat  themselves  periodically — 

2,  6,  h,  2,  6,  2,  A,  6 

and  we  see  now  that  each  carbon  atom  strikes  against  the  two  others  with 
which  it  is  directly  combined,  an  equal  number  of  times ;  in  other  words,  it 
bears  the  same  relation  to  each  of  its  neighbours.  The  ordinary  formula  for 
benzene  only  represents  the  contacts  made  during  the  first  unit  of  time,  or 
only  one  phase,  and  thus  the  view  has  sprung  up  that  the  di-derivatives  with 
the  positions  1,  2  and  1,  6  must  be  different.  If  the  above  hypothesis  or 
any  similar  one  be  considered  to  be  correct,  it  follows  that  this  difference  is 
only  apparent,  not  real." 

Thus  early  in  the  history  of  modern  structural  chemistry  did 
the  vibrational  hypothesis  make  its  appearance,  and  from  that 
time  to  the  present  day  the  view  has  slowly  grown  that  the 
intramolecular  arrangement  of  atoms  can  best  be  represented 
by  a  series  of  vibration  phases  rather  than  as  a  rigid  assemblage 
of  particles. 

The  next  stage  in  the  evolution  of  this  theory  was  taken  in 
view  of  quite  different  evidence.  The  Kekule  benzene  oscilla- 
tion had  been  put  forward  to  explain  why  two  apparently 
different  structures  had  the  same  properties ;  but  in  the  question 
of  the  acetoacetic  ester  constitution,  which  came  to  the  front 
soon  after  this,  the  crux  of  the  problem  lay  in  the  fact  that  one 
substance  reacted  as  if  it  had  either  one  or  other  of  two  totally 
different  structures. 

In  1876  Butlerow x  was  led  to  suggest  that  in  the  cases  of 
certain  bodies  a  kind  of  intramolecular  vibration  was  continually 
taking  place,  which  explained  why  some  substances  reacted 
now  in  one  way  and  again  in  another  according  to  the  type  of 
reagent  with  which  they  were  treated.  Some  years  later,  Laar 2 

1  Butlerow,  Annalen,  1870, 189,  76. 

2  Laar,  Ber.,  1885,  18,  648;  1886,  19,730. 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY          9 

collected  a  number  of  cases  in  which  by  shifting  a  hydrogen 
atom  from  one  atom  to  another  in  a  chain  it  was  possible  to 
give  some  idea  of  how  the  substances  were  able  to  act  as  if  they 
had  two  different  constitutions.  For  instance,  in  the  case  of 
acetoacetic  ester  it  is  found  that  with  certain  reagents  it  acts 
as  if  it  contained  a  hydroxyl  group,  while  with  other  substances 
it  behaves  as  if  it  were  a  pure  ketonic  compound.  This  can 
be  expressed  by  saying  that  in  the  one  instance  it  reacts  as  if  it 
had  formula  (I.),  while  in  the  other  it  appears  to  have  the 
structure  (II.)  — 

(I.)    CH3—  C:CH—  COOEt       (II.)    CH3-C—  CH2—  COOEt 
OH  O 

This  might  be  explained  by  supposing  that  what  we  call 
acetoacetic  ester  is  really  a  mixture  of  the  two  structure 
isomers  (I.)  and  (II.).  Laar  took  a  different  view.  According 
to  him,  acetoacetic  ester  was  a  simple  substance,  but  instead  of 
the  hydrogen  atom  being  attached  either  to  the  carbon  or  to  the 
oxygen  atom  it  wandered  or  vibrated  in  space  between  them, 
and  was  finally  influenced  in  its  choice  of  position  by  the  action 
of  the  reagent  applied  to  the  acetoacetic  ester.  We  may 
represent  this  by  the  following  picture  :  — 

CH3-  C  -  CH—  COOEt 


Substances  of  this  type  Laar  proposed  to  call  "  tautomeric  " 

uro,  the  same  ;  jue'/ooe,  a  part). 

This  idea  of  intramolecular  vibration,  however,  soon 
received  an  extension  by  the  discovery  of  some  cases  in  which 
substances  not  only  reacted  as  if  they  had  two  different  struc- 
tures, but  could  be  actually  isolated  in  the  two  structurally 
distinct  forms.  This  showed  that  in  some  cases  at  least  the 
Laar  hypothesis  was  incorrect,  or,  rather,  was  too  narrow  a 
statement  of  the  case;  for,  instead  of  the  wandering  atom 
remaining  always  like  Mahomet's  coffin  midway  between  two 
extremes,  in  these  cases  it  was  actually  found  at  both  ends  of 


io      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

the  vibration  range.  A  substitute  for  the  Laar  hypothesis  was 
brought  forward  by  Jacobson.1  On  his  view,  certain  substances 
may  occur  in  either  of  two  structurally  different  forms,  and  the 
change  of  one  form  into  the  other  takes  place  only  under  the 
action  of  some  reagent.  Since  any  such  change  must  be  pro- 
duced by  a  shifting  of  the  bonds  within  the  molecule,  Jacob- 
son  proposed  to  describe  the  phenomenon  by  the  name  of 
"  desmotropy  "  (Setr/joc,  bond  ;  rpo-rros,  change). 

Hantzsch  and  Herrmann 2  suggested  that  the  whole  subject 
should  be  treated  as  one,  so  that  if  a  substance  could  be  isolated 
in  two  stable  forms  it  should  be  called  desmotropic,  while  if  it 
could  not  be  so  isolated  it  should  be  termed  tautomeric.  We 
need  not  go  further  into  the  question  of  desmotropy  at  present. 
Enough  has  been  said  to  show  the  growth  of  the  idea  of  a  labile 
grouping  of  atoms  within  the  molecule,  which  at  the  present 
day  has  been  carried  as  far  as  it  can  serve  any  purpose. 

These  views  (which  we  may  call  "  dynamic  "  in  contradis- 
tinction to  the  "  static  "  conception  of  molecules  as  fixed  group- 
ings of  atoms)  did  not  come  to  a  head  in  time  to  save  Baeyer 
from  one  of  the  greatest  pieces  of  misdirected  research  which 
the  chemical  world  has  seen  in  recent  years.  The  work  itself 
is  magnificent  both  from  the  practical  and  the  theoretical  stand- 
point. But  Baeyer  carried  out  the  whole  of  his  investigations 
upon  one  assumption,  viz.  that  in  the  structural  formula  of 
benzene  there  was  a  fixed,  unalterable  arrangement  of  valencies 
which  could  be  deduced  from  the  results  of  oxidations,  reduc- 
tions, and  other  reactions.  By  this  time  many  different  modi- 
fications of  the  original  benzene  hexagon  had  come  into 
existence,  and  Baeyer  endeavoured  to  settle,  by  means  of  his 
researches,  which  one  of  these  actually  represented  the  formula 
of  benzene.  We  cannot  spare  space  to  deal  with  the  details  of 
his  work,  much  of  which  has  been  of  great  service  in  directions 
other  than  those  in  which  it  was  originally  aimed.  Finally, 
Baeyer  himself  was  driven  to  conclude  that  there  is  no  one 
formula  which  will  explain  all  the  reactions  of  benzene.  Collie 3 
has  shown  how  all  the  proposed  benzene  formulae  may  be 
harmonized  and  expressed  by  a  simple  vibrational  system  in 

1  Jacobson,  Per.,  1887,  20,  1732;  1888,  21,  2628. 
-  Hantzsch  and  Herrmann,  Ber.,  1887,  20,  2803. 
3  Collie,  Trans.  Chem.  8oc.,  1897,  71,  1013. 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY         11 

three  dimensions,  and  it  seems  unlikely  that  this  will  be 
improved  upon  to  any  great  extent.1 

From  his  examination  of  the  benzene  question,  Baeyer  was 
led  to  take  up  the  subject  of  the  terpene  constitutions,  which 
at  that  time  was  in  its  infancy.  These  substances  are  in  most 
cases  derivatives  of  reduced  benzene  rings,  so  that  Baeyer 
passed  from  the  one  subject  to  the  other  quite  naturally.  To 
his  work  in  that  line  we  owe  much  of  our  present  knowledge  of 
terpene  chemistry ;  but  we  are  even  more  indebted  to  Wallach, 
who  began  work  in  this  subject  about  the  same  time  as  Baeyer. 
We  cannot  give  even  the  briefest  summary  of  Wallach's  work 
in  the  space  at  our  disposal  here,  but  must  content  ourselves 
with  referring  the  reader  to  special  treatises  on  the  terpenes 
and  ethereal  oils. 

This  brings  us  to  the  camphor  controversy,  which  for  a 
decade  raged  through  a  corner  of  the  chemical  world.  Every 
organic  chemist  of  note  seems  to  have  considered  himself  in 
duty  bound  to  propose  some  formula  for  camphor  or  a  camphor 
derivative,  and  the  confusion  resulting  from  this  prodigality  was 
only  banished  by  the  synthesis  of  camphoric  acid  and  camphor, 
which  we  shall  describe  in  the  chapter  upon  the  dicyclic  terpenes. 

The  reader  will  now  have  some  idea  of  the  extraordinary 
fertility  of  the  theory  of  aromatic  compounds  put  forward  by 
Kekule.  We  must  next  turn  to  another  question  in  which 
Kekule,  if  not  the  actual  originator,  was  at  least  one  of  a  long 
chain  of  investigators  whose  work  has  had  a  tremendous 
influence  upon  our  ideas  of  intramolecular  arrangement. 

When  one  looks  back  upon  the  work  of  scientific  discovery, 
one  is  struck  most,  not  by  the  fact  that  certain  things  have 
been  discovered,  but  by  the  very  slightness  of  the  barrier  which 
so  often  stood  between  the  success  and  failure  of  a  certain  line  of 
research  at  a  given  period.  Again  and  again  subjects  have  been 
approached  and  their  problems  virtually  solved,  yet  for  want  of 
just  one  connecting  link,  or  even  the  addition  of  a  few  words  to 
a  statement  which  in  itself  contains  the  key  to  the  problem,  the 
question  may  go  unanswered  for  years.  No  better  example 
of  this  is  to  be  found  than  that  furnished  by  the  evolution  of 
stereochemical  theory. 

1  A  discussion  of  the  various  space  formulae  for  bcnzeue  will  be  found  in  the 
author's  "  Stereochemistry." 


12      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

In  1860  Pasteur1  carried  out  an  investigation  of  the 
tartaric  acids,  in  which  he  was  able  to  show  that  crystals  of 
dextro-  and  Isevo-tartaric  acid  are  related  to  one  another  as  an 
ohject  is  related  to  its  image  in  a  mirror.  At  this  time  the 
structure  theory  was  in  its  very  infancy,  and  Pasteur  does  not 
seem  to  have  thought  of  applying  it  to  the  case  with  which  he 
was  dealing.  He  contented  himself  with  putting  forward  as 
a  possible  explanation  the  view  that  the  atoms  in  the  tartaric 
acid  molecule  were  arranged  in  right-  or  left-handed  spirals,  or 
were  grouped  at  the  corners  of  a  tetrahedron.  This  was  the 
germ  of  the  whole  of  modern  stereochemistry,  but,  for  want  of 
a  slight  addition  to  these  expressions,  it  remained  for  later  inves- 
tigators to  reap  the  credit  of  establishing  the  correctness  of 
this  view.  In  1869  Paterno2  proposed  to  explain  certain  cases 
of  isomerism  by  means  of  tetrahedral  models.  Kekule,3  two 
years  previously,  had  described  a  tetrahedral  model,  but  it 
seems  doubtful  whether  he  really  intended  it  to  convey  an  idea 
of  the  distribution  of  valencies  in  four  directions  in  space.  No 
notice  was  taken  of  either  of  these  suggestions  by  the  chemical 
world  in  general,  and  it  appears  to  have  been  Wislicenus 4  to 
whom  we  owe  the  next  definite  pronouncement  on  the  subject. 
After  proving  that  the  structures  of  the  isomeric  lactic  acids 
were  identical,  he  added,  "  The  facts  force  us  to  explain  the 
difference  between  isomeric  molecules  of  the  same  structure  by 
a  different  arrangement  of  atoms  in  space." 

The  ultimate  solution  was  published  simultaneously  by 
Le  Bel 5  and  van't  Hoff,6  who  pointed  out  that  all  organic 
substances  showing  optical  activity  contained  at  least  one 
asymmetric  carbon  atom,  i.e.  an  atom  whose  four  valencies  are 
attached  to  four  dissimilar  groups.  A  slight  extension  of  the 
theory  sufficed  to  explain  the  occurrence  of  isomeric  substances 
containing  a  double  bond ;  and  Baeyer 7  applied  it  also  to  the 

1  Pasteur,  "  Recherches    sur    la  dissymmetric    inoleculaire    des    produits 
organiques  naturels." 

2  Paterno,  "  Giorn.  di  Scienze  Naturali  ed  Econ."    V.     Palermo,  1869. 

3  Kekule',  Zeitsch.f.  Chem.,  1867,  N.F.,  3,  217. 

4  Wislicenus,  Annalen,  1873,  167,  343. 

5  Le  Bel,  Bull  soc.  chim.,  1874,  II,  22,  377. 

6  Van't  Hoff,  "  Voorstell  tot  uitbreiding  der  structuur  formulas  in  de  ruinate." 
Utrecht,  1874. 

7  Baeyer,  Ber.,  1885, 18,  2277. 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY         13 

case  of  cyclic  substances.  But  the  theory  has  been  by  no 
means  limited  to  carbon  compounds  alone.  In  1890  Hantzsch 
and  Werner1  had  recourse  to  stereochemical  ideas  to  explain 
cases  of  isomerism  among  the  oximes;  in  1893  Werner  was 
able  to  bring  some  semblance  of  order  into  the  class  of  metal- 
ammonia  derivatives;  while  in  1894  Hantzsch2  put  forward  a 
theory  of  the  diazo-group.  On  the  side  of  the  question  dealing 
with  optical  rotatory  power,  the  work  of  Le  Bel 3  on  nitrogen, 
Smiles4  on  sulphur,  Pope  and  his  students5  on  selenium  and 
tin,  and  Kipping6  on  silicon,  have  shown  that  asymmetric 
atoms  of  these  elements  may  also  give  rise  to  activity. 

So  much  for  the  statical  side;  but  there  is  another  point 
of  view  from  which  we  may  regard  the  relations  between  the 
positions  of  atoms  in  space.  In  this  new  field  Victor  Meyer  and 
Bischoff  have  contributed  by  far  the  greatest  additions  to  our 
knowledge.  They  have  shown  that  reactions  may  be  hindered,  or 
even  completely  impeded,  by  certain  groupings  of  atoms  in  given 
positions.  For  example,  if  in  benzoic  acid  we  substitute  methyl 
groups  for  the  two  hydrogen  atoms  in  the  ortho-positions  to  the 
carboxyl  group,  the  acid  becomes  at  once  much  more  difficult 
to  esterify.  This  phenomenon  is  termed  "  steric  hindrance." 

We  have  not  space  to  enter  into  any  question  of  stereo- 
chemistry in  detail  at  present ;  but  in  this  connection  we  must 
mention  one  of  the  greatest  pieces  of  research  which  have  been 
carried  out  in  the  past  twenty  years.  When  Emil  Fischer  and 
his  students  first  began  methodically  to  examine  the  sugars,  the 
investigation  of  that  class  of  bodies  was  regarded  as  one  of 
the  most  hopeless  problems  which  an  organic  chemist  could 
set  himself.  The  substances  were  often  uncrystallizable,  and 
differed  so  little  among  themselves  that  it  seemed  hopeless 
to  try  to  separate  one  isomer  from  a  mixture.  Further,  the 
enormous  complication  of  their  isomerism,  due  to  the  numerous 
asymmetric  carbon  atoms  they  contain,  seemed  to  make  the 
attack  upon  this  branch  of  stereochemistry  one  of  the  least 

Hantzsoh  and  Werner,  Ber.,  1890,  23,  11. 
Hantzsch,  Ber.,  1894,  27,  1702. 
Le  Bel,  C.  B.,  1891, 112,  724;  1901,  129,  548. 
Smiles,  Trans.  Chem.  Soc.,  1900,  77,  1174. 

Pope  and  Peachey,  Proc.  Chem.  Soc.,  1900,  16,  42,  11G;  Pope  and  Neville, 
Trans.  Chem.  Soc.,  1902,  81,  1552. 

6  Kipping,  Tram.  Chem,  Soc.,  1907,  91,  209,  717;  1908,  93,  457 ;  1909,  95, 69. 


14      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

promising.  There  seems  no  doubt  that  with  ordinary  means 
at  his  disposal  Fischer  could  never  have  accomplished  the 
work ;  but  his  genius  had  stood  him  in  good  stead  in  one  of  his 
earlier  researches.  In  1877  he  discovered  the  compound 
phenylhydrazine,1  and  by  means  of  this  substance  he  was  able 
to  convert  the  imperfectly  crystallizable  sugars  into  crystalline 
hydrazones,  from  which  he  was  able  to  regain  the  sugar  after 
he  had  thus  separated  it  from  its  isomers.  In  a  few  years 
Fischer2  completed  this  vast  research,  in  the  course  of  which 
he  established  the  configurations  of  all  the  pentoses  and  hexoses 
by  experimental  means  and  by  reasoning  which  is  unlikely  to 
be  surpassed  for  simplicity  and  directness. 

After  leaving  the  sugars,  Fischer  devoted  his  attention  to 
the  purine  group,  in  which  he  carried  out  a  series  of  brilliant 
syntheses ;  and  when  this  subject  in  its  turn  was  exhausted  he 
attacked  the  problem  of  the  decomposition  products  of  the 
peptones,  with  results  which  are  described  in  a  later  chapter  of 
the  present  volume. 

There  are  one  or  two  other  problems  which  have  been  dealt 
with  in  the  last  thirty  years,  but  they  are  somewhat  dis- 
connected with  each  other  and  with  the  parts  of  organic 
chemistry  which  have  just  been  described. 

In  the  first  place,  there  is  the  pyridine  question.  After  the 
constitution  of  benzene  had  been  established,  it  was  inevitable 
that  the  same  view  would  sooner  or  later  be  applied  to  pyridine, 
and  in  1869  Korner3  proposed  to  represent  that  substance  by 
a  benzene  ring  in  which  one  of  the  — CH=  groups  was 
replaced  by  a  nitrogen  atom.  This  theory  was  supported  by 
some  researches  of  Kekule,4  and  is  to-day  accepted  as  correct. 
Now,  the  importance  of  pyridine  and  its  simple  derivatives  does 
not  lie  in  themselves,  but  rather  in  the  fact  that  the  pyridine 
ring  appears  to  form  the  basis  of  all  the  natural  alkaloids,  just 
as  the  benzene  ring  is  the  foundation  of  the  aromatic  series. 
We  need  not  enter  into  the  alkaloid  question  here,  as  a 
chapter  in  this  volume  is  devoted  to  it. 

1  Fischer,  Annalen,  1877, 190,  81. 

2  Fischer,  Ber.,  1894,  27,  3189. 

3  The  first  publication  of  this  idea  seems  to  be  due  to  Dewar,  Zzit.f.  Chem., 
1871,  117. 

4  Kekule',   Ber.,   1890,  23,   564;    £ee  also  Bichter-Anschutz,  Lahrbuch  d. 
Organ.  Chemie,  1905,  II.  711,  712. 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY         15 

Since  the  time  of  Kekule,  organic  chemistry  has  been  for 
the  most  part  a  synthetic  science.  At  the  present  day  con- 
siderably over  a  hundred  thousand  organic  compounds  are 
known,  and  one  need  not  have  the  least  hesitation  in  saying 
that  if  seventy  per  cent,  of  them  had  never  been  synthesized 
we  should  not  feel  the  lack  of  them  to  any  appreciable  extent. 
The  reason  for  this  enormous  flood  of  synthetic  material  is  to 
be  found  in  the  German  University  system ;  for  since,  under  the 
German  regulations,  the  degree  in  chemistry  is  granted  only  on 
the  results  of  original  research,  it  follows  that  every  Ph.D. 
represents  so  many  new  compounds — at  least,  as  a  general 
rule.  But  these  do  not  include  all  the  forces  leading  to  the 
steady  pursuit  of  the  synthetic  branch.  The  great  German  dye 
industry  employs  in  itself  hundreds  of  chemists,  and  from  them 
also  flows  a  steady  stream  of  new  compounds.  The  same  may 
be  said  of  the  explosive  manufacturers  and  the  firms  which 
produce  synthetic  drugs. 

Before  closing  this  chapter  we  may  cast  a  glance  at  the 
physical  methods  which  have  sprung  up  in  organic  chemistry 
during  the  last  half-century.  The  relation  between  chemical 
constitution  and  optical  rotatory  power  dates,  of  course,  from 
the  time  of  van't  Hoff  and  Le  Bel's  papers  on  the  asymmetric 
carbon  atom;  and  Guye1  has  propounded  a  theory  which, 
though  failing  in  detail,  seems  not  inapplicable  to  the  general 
connection  between  rotation  and  constitution.  Eefractive  index 
appears  to  be  a  property  which  is  closely  connected  with  the 
mode  of  linkage  of  the  atoms  in  organic  compounds,  and  much 
work  has  been  done  in  this  line  by  Briihl  and  others.  The 
electrical  conductivities  of  acids  depend  very  greatly  upon  the 
constitution  of  the  radical  to  which  the  carboxyl  group  is 
attached.  Magnetic  rotation,  i.e.  the  optical  rotatory  power 
which  nearly  all  substances  acquire  when  placed  in  strong 
magnetic  fields,  has  been  studied  in  great  detail  by  the  late 
Sir  W.  H.  Perkin,  who  showed  that  by  its  aid  the  constitution 
of  many  substances,  especially  desmotropic  bodies,  could  be 
determined.  Absorption  spectra,  both  optical  and  electric,  have 
been  used  in  the  determination  of  doubtful  structures ;  the  first 
have  been  employed  by  Hartley,  the  second  by  Drude. 

We  have  now  completed   our   survey  of  modern   organic 

1  Guye,  C.  It,,  1890,  110,  714. 


1 6      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

chemistry.  It  has,  of  course,  been  impossible  to  deal  with 
many  pieces  of  work  which  are  quite  as  important  as  some  of 
those  we  have  actually  mentioned,  but,  on  the  whole,  it  is 
believed  that  a  more  or  less  accurate  picture  has  been  given  of 
the  evolution  of  the  subject  along  various  lines.  If  we  look 
only  to  the  principles  which  lie  at  the  back  of  the  science  and 
which,  though  they  may  remain  unformulated,  still  sway  our 
views  by  some  sub-conscious  action,  we  shall  find  that  the 
history  of  the  last  five  and  twenty  years  has  been  one  of  a 
gradual  passing  from  a  static  to  a  dynamic  view  of  the  molecule. 
In  the  early  days,  the  ideas  of  chemists  centred  round  more  or 
less  rigid  structures  which  they  regarded  as  approximately 
"set."  The  tetrahedron  of  van't  Hoff  had  the  effect  of 
strengthening  rather  than  weakening  this  tendency ;  and  it  is 
much  to  be  regretted  that  the  van't  Hoff  view,  rather  than 
that  of  Le  Bel,  found  favour  in  the  chemical  world  at  large. 
At  this  period  the  state  of  mind1  of  the  average  organic 
chemist  seems  to  have  been  somewhat  similar  to  that  of  the 
student  who,  when  asked  to  explain  the  atomic  theory,  said, 
"  Atoms  are  square  blocks  of  wood  invented  by  Dr.  Dalton." 

This  view  of  the  subject  was  shaken  by  the  publication  of 
Werner's  views  on  affinity  and  valency,2  in  which  the  idea 
of  directed  valencies  was  shown  conclusively  to  be  a  quite 
unnecessary  assumption ;  and  at  the  present  day  the  idea  of  a 
certain  amount  of  intramolecular  "  play  "  is  not  regarded  as 
absolute  anathema  by  the  more  advanced  school. 

The  last  twenty  years  of  organic  chemistry,  however,  have 
been  rather  barren  in  many  directions.  The  only  really  out- 
standing conception  which  has  been  evolved  and  developed 
into  several  branches  has  been  the  idea  of  the  arrangement  of 
atoms  in  space.  Apart  from  this,  the  theoretical  side  of  the 
subject  has  not  given  rise  to  anything  more  than  a  series  of 
very  minor  theories,  none  of  which  (with  the  exception  of 
Thiele's  partial  valency  hypothesis)  seems  likely  to  develop 
in  any  wide  manner.  The  reason  for  this  is  most  probably 
to  be  sought  in  the  recent  and  sudden  rise  of  physical 
chemistry,  which  has  drawn  away  from  the  organic  field  many 

1  If  this  statement  appears  exaggerated,  the  reader  is  recommended  to 
consult  the  Annalen,  1901,  316,  71,  where  he  will  find  ample  evidence  of  the 
persistence  of  these  views  even  quite  recently  in  certain  circles. 

2  Werner,  "  Beitrage  zur  Theorie  der  Affinitat  und  Valenz."     1891. 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY         17 

chemists  who  would  doubtless  have  carried  the  older  branch 
much  further  forward  than  has  been  possible  without  their 
assistance. 

The  progress  of  human  thought  has  been  likened  by  some 
author  to  the  journey  of  a  passenger  on  a  funicular  railway. 
We  leave  the  starting-point  in  the  valley  and  pass  upward 
through  tunnels  and  cuttings  for  a  time,  until  at  last  we  emerge 
again  into  daylight  to  find  that  though  we  are  still  within  a 
stone's  throw  of  our  point  of  departure  we  have  moved  in  a 
spiral,  and  now  look  down  from  a  new  point  of  view  at  the 
station  which  we  have  left.  In  the  same  way,  science  appears 
to  progress  in  cycles;  and,  after  a  more  or  less  prolonged 
period,  we  find  the  old  views  reappearing  and  the  old  con- 
flicts beginning  once  more,  though  at  each  new  encounter 
the  point  of  view  is  slightly  shifted  as  new  or  more  refined 
experimental  methods  replace  or  supplement  the  older  ones. 

This  periodicity  in  theory  has  seldom  been  displayed  more 
clearly  than  in  the  matter  of  structural  formulae  and  their 
meaning.  If  we  examine  the  views  of  the  two  pioneers  Couper 
and  Kekule,  we  find  that,  though  agreed  as  to  the  method  of 
writing  down  formulae,  they  were  by  no  means  at  one  as 
regards  what  the  formulas  expressed  when  once  put  upon 
paper.  Kekule's  view *  was  based  upon  quite  incontrovertible 
reasoning : — 

"  Rational  formulse  are  decomposition  formulse,  and  in  the  present  state 
of  chemical  science  can  be  nothing  more.  These  formulse  give  us  pictures 
of  the  chemical  nature  of  substances ;  because  the  manner  of  writing  them 
indicates  the  atomic  groups  which  remain  unattacked  in  certain  reactions. 
.  .  .  Every  formula  which  expresses  definite  metamorphoses  of  a  compound 
is  rational;  that  one  of  the  different  rational  formulae  is  the  most  rational, 
which  expresses  the  greatest  number  of  these  metamorphoses." 

Couper,2  on  the  other  hand,  put  the  case  as  follows : — 

"  Gerhardt  ...  is  led  to  think  it  necessary  to  restrict  chemical  science  to 
the  arrangement  of  bodies  according  to  their  decompositions,  and  to  deny  the 
possibility  of  our  comprehending  their  molecular  constitution.  Can  such  a 
view  tend  to  the  advancement  of  science  ?  Would  it  not  be  only  rational,  iu 
accepting  this  veto,  to  renounce  chemical  research  altogether  ?  " 

Thus,  on  the  one  side,  we  have  Kekule  maintaining  that 

1  Kekule,  AnndUm,  1858,  106,  149. 

2  Couper,  Phil.  Mag.,  1858,  IV.  16,  107. 


18      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

graphic  formulae  are  simply  shorthand  symbols  by  means  of 
which  we  can  easily  and  compactly  express  the  results  of  our 
chemical  experiments ;  while,  on  the  other  side,  Couper  claims 
that  these  ciphers  give  us  the  key  to  the  actual  mode  of  linkage 
of  the  atoms  within  the  molecule. 

These  two  theories  still  persist  side  by  side  in  the  present- 
day  chemical  world,  and  a  considerable  waste  of  energy  occurs 
when  two  upholders  of  different  views  try  to  interpret  the  same 
set  of  results.  The  conflict  between  the  two  schools  has  become 
especially  acute  within  recent  years  owing  to  the  strides  which 
have  been  made  in  the  correlation  of  chemical  constitution  and 
physical  properties  of  compounds ;  for  a  substance  may  react 
as  though  it  possessed  a  given  constitution,  whereas  physical 
measurements  would  lead  us  to  quite  different  conclusions  with 
regard  to  the  atomic  linkages  of  the  molecule  in  question.  In 
the  case  of  a  chemical  problem,  it  seems  evident  that  chemical 
evidence  should  carry  most  weight,  and  the  confusion  of  ideas 
has  been  chiefly  due  to  workers  on  the  physical  side  employing 
chemical  formulae  to  denote  something  which  is  not  chemical. 
It  seems  a  peculiar  process  of  reasoning  which  allows  a  person 
to  base  his  hypotheses  upon  the  reaction  formulae  of  chemists, 
and  then,  after  taking  into  account  some  physical  property  of  a 
substance,  to  return  to  chemistry  with  a  proof  of  the  incorrect- 
ness of  the  original  reaction  formulae  upon  which  his  argumen- 
tation is  based. 

When  we  look  at  the  present  condition  of  organic  chemistry 
it  is  rather  discouraging.  Everything  seems  to  be  cut  and 
dried  as  far  as  the  theory  of  the  subject  is  concerned,  and  on 
the  practical  side  the  main  tendency  seems  to  be  merely  to 
confirm  current  theories.  It  is  self-evident  that  we  can  make 
no  progress  by  confining  ourselves  to  the  confirmation  of  the 
views  which  pass  muster  at  present.  If  any  advance  is  to  be 
made,  it  must  be  begun  by  investigating  those  phenomena  which 
do  not  agree  with  the  standard  theory  ;  and,  as  an  instance,  we 
might  point  to  the  case  of  the  ionic  hypothesis  and  the  ordinary 
organic  reaction.  There  is,  however,  another  direction  in  which 
we  may  look  for  a  line  of  research.  It  is  customary  in  text- 
books to  assume  that  "  water  adds  on  in  such  and  such  a  way," 
or,  "  the  bromine  atom  attaches  itself  in  the  usual  way  to  the 
tertiary  carbon  atom "  ;  many  such  expressions  can  be  found, 


MAIN  CURRENTS  IN  ORGANIC  CHEMISTRY         19 

but  it  never  seems  to  occur  to  the  ordinary  person  that  to  state 
a  fact  is  not  to  offer  an  explanation,  and  while  we  are  all  suffi- 
ciently glib  in  describing  how  a  reaction  takes  place,  very  few 
of  us  seem  to  give  a  thought  to  the  problem  of  why  the  reaction 
takes  that  particular  course  rather  than  another.  We  have 
thus  accumulated  an  immense  mass  of  data  concerning  the 
results  of  reactions,  but  very  little  indeed  with  regard  to  their 
causes.  It  seems  obvious  that  if  organic  chemistry  is  to  get  a 
new  lease  of  life,  some  attention  must  be  paid  to  such  questions 
as  these.  Of  course  the  investigator  who  takes  up  such  pro- 
blems will  have  to  invent  a  new  set  of  methods  ;  but  the  aim 
in  view  would  be  worth  a  little  trouble. 

At  the  present  day  it  appears  to  be  the  fashion  to  suppose 
that  certain  views  are  so  firmly  established  that  no  research 
into  their  foundations  is  worth  the  labour  expended  on  it,  and 
consequently  investigators  devote  much  time  and  energy  to  the 
examination  of  highly  complex  substances  while  simpler  com- 
pounds are  supposed  to  be  "  worked  out."  In  the  same  way  it 
was  supposed  for  many  years  that  the  composition  of  the 
atmosphere  was  well  known,  until  the  work  of  Eamsay  and 
Eayleigh  showed  how  little  we  knew  of  even  this  common 
mixture.  With  this  object  lesson  before  them,  it  is  to  be 
hoped  that  more  organic  chemists  will  find  time  to  investigate 
some  of  the  problems  which  are  passed  over  by  the  mass  of 
workers  who  seem  to  place  a  label  in  the  same  category  as  an 
explanation. 


CHAPTER  II 

THE  POLYMETHYLENES 

IN  the  succeeding  chapters  we  shall  deal  with  the  mono-  and 
di- cyclic  systems  which  are  found  among  the  terpenes  and 
camphors;  but  before  entering  upon  a  discussion  of  these  it 
appears  desirable  to  give  some  account  of  the  root-substances 
from  which  all  of  them  are  derived.  The  present  chapter, 
therefore,  will  be  devoted  to  the  polymethylenes. 

Compounds  of  this  class  have  the  general  formula  (CHa),,, 
where  "n"  is  any  integer  from  three  to  nine;  and  they  are 
therefore  isomeric  with  the  open-chain  olefinic  compounds  of 
the  general  formula  CnH2n.  The  two  classes  differ  widely 
from  each  other,  both  in  chemical  and  in  physical  properties ; 
this  point  will  be  discussed  in  detail  later  in  the  chapter. 

Two  nomenclatures  are  at  present  in  vogue  for  derivatives 
of  this  class  of  compounds.  In  the  first,  the  given  substance  is 
distinguished  as  a  tri-,  tetra-,  penta-  hexa-,  hepta-,  octo-,  or  nono- 
methylene  according  as  its  ring  is  made  up  of  three,  four,  five, 
six,  seven,  eight,  *or  nine  methylene  groups.  If  a  carbonyl 
group  occurs  in  the  ring,  its  presence  is  indicated  by  the  prefix 
"  keto-,"  while  for  a  carboxyl  group  the  suffix  "  -carboxylic  acid  " 
is  added  to  the  name  of  the  polymethylene.  The  second  system 
of  nomenclature  is  a  more  general  one.  The  designation  of 
any  polymethylene  is  found  on  this  second  system  by  taking 
the  name  of  the  corresponding  paraffin  and  prefixing  "  cyclo-  " 
to  it.  When  a  double  bond  occurs  in  the  compound  the 
termination  "  ane  "  is  changed  to  "  ene  " ;  and  for  two  double 
bonds  to  "  di-ene."  If  a  ketonic  group  occurs  in  the  molecule 
it  is  distinguished  by  changing  the  termination  "ane"  to 
"  anone."  As  can  be  seen,  both  systems  are  somewhat  clumsy, 
and  hence  it  is  desirable  at  times  for  the  sake  of  clearness 
to  use  the  one  which  most  simply  expresses  the  compound 


THE  POLYMETHYLENES  21 

in  question.     The  following  examples  will  help  to  make  the 
matter  clearer  :— 

CH2 

CH2  CH2—  CH  CH        CH 

/    \  I          II  II  II 

CH2  -  CH2  CH2—  CH  CH  -  CH 

Trimethylene  Cyclobutene.  Cyclopentadiene. 

Cyclopropane. 

CO 

CH2—  CH.COOH  CH2    CH2 

OH  —  Oil 


Tetramethylene-carboxylic  acid.  Ketopentaraethylene 

Cyclobutane-carboxylic  acid.  Cyclopentanone. 

There  are  at  present  ten  principal  methods  by  which  we  can 
obtain  saturated  cyclic  carbon  compounds  ;  of  these,  only  four 
yield  simple  polymethylenes  ;  two  others  produce  homologues  of 
the  parent  substances  ;  and  the  remaining  methods  lead  to  the 
formation  of  acids  with  a  polymethylene  nucleus.  We  may 
examine  all  these  reactions,  and  for  the  sake  of  convenience  in 
future  reference  it  may  be  well  to  number  them  consecutively. 

(1)  The  simplest  method  of  obtaining  a  polymethylene  com- 
pound is  to  act  upon  the  corresponding  open-chain  dihalogen 
derivative  with  zinc  dust  or  sodium.  This  is  merely  a  modifi- 
cation of  the  ordinary  Fittig-Wiirtz  reaction— 


)Ho 


CH2Br  CH2 

a=  21sraBr4.H2C 
CH2Br  CH2 


(2)  When  the  calcium  salt  of  a  mono-basic  acid  is  distilled 
it  yields  calcium  carbonate  and  a  ketone.  The  same  reaction 
was  employed  by  Wislicenus  and  Hentzschel l  in  the  case  of  a 
dibasic  acid;  and  the  resulting  compound  was  found  to  be  a 
cyclic  ketone — 

1  Wislicenus  and  Hentzschel,  Annalen,  1893,  275,  312. 


22      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 
CH2.CH2.CO.O  CH2. 


CO 


Ca  =  CaCOo  + 


CH2.CH2.CO.O  CH2.C1 

From  the  ketone  the  corresponding  secondary  alcohol  was  pre- 
pared by  reduction  with  sodium  in  ethereal  solution :  and  from 
the  alcohol,  by  the  action  of  hydriodic  acid  at  0°  C.,  the  iodide 
was  formed.  This,  on  reduction  with  zinc  and  hydrochloric 
acid,  gave  the  corresponding  hydrocarbon — 

.  OH2  \j xi  2 .  Cxi  2 

CH .  OH > 

/ 


\ 


CO 


CH2 .  C 


CH2 


CH2 

CH.I 


CH2 .  CH2 

\ 


CH2 .  GH2 


CH, 


CH2.C 


(3)  If  the  unsaturated  cyclic  hydrocarbon  corresponding  to 
the  desired  polymethylene  is  known,  the  saturated  compound 
may  be  obtained  from  it  by  passing  its  vapour,  mixed  with  a 
stream  of  hydrogen,  over  finely  divided  nickel.     This  method 
was  devised  by  Sabatier  and  Senderens.1     The  nickel  is  heated 
while  the  gas  is  passed  over  it,  the  temperature  being  regulated 
with  care,  as  the  action  is  apt  to  be  carried  too  far  and  to  lead  to 
the  opening  of  the  ring  by  further  reduction  of  the  polymethylene. 

(4)  In  those  cases  in  which  it  is  possible  to  obtain  the 
amine  derived  from  the  required  polymethylene,  it  can  be  con- 
verted into  the  parent  substance  by  Kishner's  method.2     In 
the  first  place,  the  amine  is  converted  into  the  hydrazine  by 
bromination  and  subsequent  treatment  with  silver  oxide ;  the 
hydrazine  is  then  oxidized  with  alkaline  potassium  ferricyanide. 
Nitrogen  is  finally   evolved,   and    the    required  hydrocarbon 
remains  behind.     For  the  sake  of  simplifying  the  formulae  we 
may  take  the  theoretical  case  of  the  production  of  tetramethy- 
lene  from  amidotetramethylene ;  the  steps  in  the  reaction  are 
indicated  below — 

1  Sabatier  ani  Senderens,  C.  R.,  1901,  132,  210. 

2  Kishner,  J.  pr.  Ch.,  1895,  II.,  52,  424. 


THE  POLYMETHYLENES 

J?      w? 

in 

£3 O 


H 


W     W 
o—  o 


— O 

t 


S-o 


0—0 

M-^  •— — 

o—o 


8-8 


o 


W 


— -     "~~" 
o—o 

hri       &3 
0—0 


24  y    RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

(5)  The  foregoing  methods  lead  direct  to  the  simple  poly- 
methylenes,  but  homologous  compounds  may  be  prepared  in 
other  ways.  For  instance,  the  reaction  of  pinacone  formation 
may  be  modified  in  such  a  way  as  to  give  us  cyclic  alcohols. 
In  the  case  of  ordinary  pinacone  syntheses  two  molecules  of 
a  ketone  unite  during  the  reduction  process.  If  for  the  two 
ketone  molecules  we  substitute  a  single  molecule  of  a  diketone 
the  reaction-product  will  in  this  case  also  be  a  pinacone  ;  and 
in  some  cases  two  pinacones  are  formed,  one  an  open-chain 
compound,  the  other  a  polymethylene  derivative.  For  example, 
Kipping  and  Perkin,1  by  the  reduction  of  diacetyl-pentane, 
obtained  a  mixture  of  dihydroxy-nonane  (I,)  and  dimethyl- 
dihydroxyheptamethylene  (II.). 

,CH2 .  CH2 .  CH(OH) .  CH3 
CH2  (I.) 

/CH2 .  CH2 .  CO .  CH3  /  \CH2 .  CH2 .  CH(OH) .  CH3 
CH 

CH2 .  CO .  CH3^       /CH2 .  CH2 .  C(OH) .  CH3 


CH2 


\CH2.CH2.C(OH).CH3 


(II.) 


The  hydrocarbon  may  then  be  prepared  from  the  pinacone 
in  the  usual  way. 

(6)  The  Grignard  reaction  has  been  applied  to  the  pro- 
duction of  polymethylene  homologues  by  Zelinsky  and  Moser,2 
who  prepared  methylpentamethylene  from  w-aceto-butyl  iodide 
by  the  action  of  magnesium.  The  reaction  takes  place  in  the 
following  steps : — 


CHg.CO 

H2C 
H,n 

I 

CH2 

1 

CHg.CO 

H2C 
HP 

Mgl 
CH2 
ill 

CHg.C.O.Mgl 
H2C         vx'Jtl2 
Hn          PTT,, 

2 
CH3. 

H*C 
TT_P 

C.OH 
CH2 

PIT- 

CH3 
KsC 

.C.H 

/\ 
CH2 

PR. 

1  Kipping  and  Perkin,  Trans.  CJiem.  Soc.,  1890,  57,  241. 

2  Zelinsky  and  Moser,  Ber.,  1902,  35,  2684. 


THE  POLYMETHYLENES  25 

(7)  Buchner  and  Curtius l  were  the  first  to  point  out  that 
the  aliphatic  diazo- compounds  had  the  faculty  of  coupling  with 
unsaturated  substances  to  yield  pyrazole  or  pyrazoline  deriva- 
tives. These  latter  bodies,  on  distillation,  break  down  into 
nitrogen  and  trimethylene  compounds.  For  example,  in  the 
case  of  diazomethane  and  fumaric  ester  the  reaction  takes  the 
following  course : — 

CH2         CH.COOEt        CH2— CH.COOEt 

\     +    II  =1  I 

N  =  N         CH.COOEt       N        CH.COOEt 

v  \ 

.  COOEt 
COOEt 


Nje, 


(8)  The  remaining  methods  with  which  we  have  to  deal 
depend  upon  such  reactions  as  the  acetoacetic  or  malonic  ester 
condensations.  It  is  obvious  that  just  as  we  obtained  a  cyclic 
ketone  by  substituting  the  calcium  salt  of  a  dibasic  for  that  of 
a  monobasic  acid,  we  could  obtain  an  intramolecular  condensa- 
tion by  substituting  for  acetic  ester  the  ester  of  a  dibasic  acid. 
For  example,  if  we  used  adipic  ester,  and  proceeded  in  the 
same  way  as  in  the  ordinary  acetoacetic  ester  synthesis,  we 
should  obtain  a  keto-pentamethylene  carboxylic  ester — 

CH2.CO.OEt 
|  -  Eton 

i          i  — >  CH2.CO.OEt 

OH..  <!o 


CH2.CH2.CH.CO.OEt  CH2 .  CH2 .  CH .  CO  .  OEt 

|  -Eton      i  I 

|H I  — >    CH2 CO 

CH2—  COJ  OEt  I 

(9)  Again,  if  we  condense  oxalic  ester  with  a  dicarboxylic 
ester  by  means  of  sodium  ethylate  we  can  obtain  a  diketo- 
polymethylene  dicarboxylic  ester — 

1  Buchner  and  Curtius,  B&r.,  1885, 18,  237. 


26      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 
CO  j  OEt  H^-OH .  COOEt  CO CH .  COOEt 

\  -2EtOH 


CH2 


CH 


0  i  OEt  H4-CH .  COOEt  CO CH .  COOEt 

(10)  The  last  series  of  methods1  which  we  need  describe 
depends  upon  the  interaction  of  alkyl  halogen  compounds  with 
the  sodium  derivatives  of  malonic,  acetoacetic,  or  ethylene 
tetracarboxylic  ester.  Some  examples  will  serve  to  make  the 
matter  clear — 

CH2.Br  COOEt  CH2     COOEt 

C  C  +        2NaBr 


COOEt  CH2      COOEt 


CH2.Br 

CH2.Br  Na . CH . COOEt  CH2 CH. COOEt 

|  |  =||+        NaBr 

CH2.Br          CO.CH3  CH2.Br  CO.CH3 

This  bromine  compound  may  now  react  with  more  sodium 
ethylate  in  either  of  two  ways,  yielding  in  the  one  case  a 
trimethylene  derivative,  and  in  the  other  an  internal  ether — 

COOEt  COOEt 

I  I 

CH2 C— CO .  CH3          >      CH2— C— CO .  CH3 


CH2.BrNa  CH2 

Ketonic  form. 

CH2 C .  COOEt  CH2 C .  COOEt 

I  II  >      I  II 

CH2Br  NaO .  C .  CH3  CH2— 0—  C .  CH3 

Enolic  form. 

The  reaction  between  an  alkylene  dibromide  and  the  disodium 
derivative  of  ethane  tetracarboxylic  ester  takes  place  as 
follows  :— 

CH2.Br          Na.C(COOEt)2          CH2— C(COOEt)2 

I  4-  =|  +2NaBr 

CH2 .  Br         £Ta .  C(COOEt)2         CH2— C(COOEt)2 

1  Perkin,  Ber.,  1884,  17,  54 ;  Perkin  and  Freer,  Tram.  Chem.  Soc,,  1887,  51, 
833;  Baeyer  and  Perkin,  Ber.,  1884,  17,  448  ;  Perkin,  Trans.  Chem.  Soc.,  1888, 
53,1. 


H  =  CH 


THE   POLYMETHYLENES  27 

This  method  may  be  modified  by  substituting  for  the  ethane 
tetracar  boxy  lie  ester  an  alkylene  dimalonic  ester  and  using 
iodine  instead  of  the  alkyl  halide  — 

Na  .  C(COOEt)2  C(COOEt)2 

Ia+  C 

/ 

Na  .  C(COOEt)2  C(COOEt)2 

We  must  now  deal  with  the  individual  members  of  the 
polymethylene  series. 

The  simplest  member  of  the  group,  trimethylene,  was  dis- 
covered by  Freund,1  who  prepared  it  by  the  action  of  sodium 
upon  trimethylene  bromide  — 

CH2.Br  CH2 

-f        2NaBr 


CH2. 


H2  +  Naa  =  CH2 

Br  CH2 


It  is  a  gas  at  ordinary  temperatures,  melts  at  —126°  and 
boils  at  -35°  approximately  under  a  pressure  of  749  mm.2 
Trimethylene  is  isomeric  with  propylene,  from  which  it  can  be 
distinguished  by  means  of  halogens  or  halogen  acids.  In  the 
case  of  the  polymethylene,  chlorine  breaks  the  ring  and  pro- 
duces trimethylene  chloride  ;  while  propylene  takes  up  chlorine 
to  form  propylene  dichloride— 


CIL 


I-  C12=CH2 
CH2  CH2C1 


The  next  member  of  the  series,  tetramethylene,  has  been 
known  only  within  recent  years,  though  for  twenty  years 
attempts  to  prepare  it  had  been  made  by  various  workers,  but 
without  success.  It  was  at  last  produced  by  Wills  tatter 
and  Bruce  3  in  the  following  way.  Tetramethylene  carboxylic 
acid  (I.)  was  first  prepared,  for  it  should  be  noted  that  though 

1  Freund,  Monatsh.,  1882,  3,  625  ;  J.  pr.  Ch.,  1885,  II.  26,  367. 

2  Ladenburg  and  Kriigel,  Ber.,  1899,  32,  1821. 

3  Willstatter  and  Bruce,  Ber.,  1907,  40,  3979. 


28      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 


the  parent  substance  was  unknown,  many  tetramethylene 
derivatives  had  been  prepared  by  the  general  methods  given 
above.  This  acid  was  converted  into  the  amide  (II.),  and  this, 
by  the  usual  reaction  with  bromine  and  soda,  gave  the  amine 
(III.).  From  this,  by  methylation,  tetramethylene-trimethyl- 
ammonium  hydroxide  (IV.)  was  obtained,  which,  on  distillation, 
broke  down  into  various  compounds,  the  only  one  which  concerns 
us  being  the  cyclobutene  (V.).  When  this  body  is  reduced  by 
the  Sabatier  and  Senderens  method,  passing  it  with  a  stream  of 
hydrogen  over  nickel  powder  at  a  temperature  not  exceeding 
100°,  it  is  converted  into  tetramethylene  (VI.). 


CH2  .  CH  .  COOH         CH2  .  CH  .  CO  .  NH2  CH2  .  CH  .  NH2 

0x12  •  0x12  Ori2  .  Oil2  0x12  .  OlJ2 

(I.)  (II.)  (III.) 

CH2.CH.N(CH3)3OH         CH2.CH  CH2.CH2 


LL 


CH2.CxI 
(IV.)  (V.)  (VI.) 

Tetramethylene  is  a  gas  at  ordinary  temperatures,  but  con- 
denses to  a  liquid  with  a  boiling-point  of  11°-12°  C.  It  does 
not  solidify  even  at  -  80°  C. 

Pentamethylene  was  first  produced  by  Wislicenus  and 
Hentzschel  by  the  second  general  method  given  above.  It  is 
a  light  liquid,  boiling  at  50°  C.,  and  remaining  unsolidified  at 
-80°  C.  It  is  found  to  occur  naturally  in  Caucasian1  and 
also  in  American 2  petroleum. 

Hexamethylene  was  first  synthesized  by  Baeyer3  by  the 
reduction  of  1,  4-diketo-hexamethylene.  Perkin  and  Haworth 4 
produced  it  by  the  action  of  sodium  upon  a  boiling  alcoholic 
solution  of  di-bromo-hexamethylene,  and  it  is  also  formed  by 
the  reduction  of  benzene.  It  is  a  pleasant-smelling  liquid, 
boiling  at  81°  C.,  and  solidifying  to  a  solid  of  melting- 
point  6°  C. 

1  Markownikoff,  Ber.,  1897,  30,  974. 

2  Young,  Trans.  Chem.  Soc.,  1898,  73,  906. 

3  Baeyer,  Annalen,  1894,  278,  111. 

*  Perkin  and  Haworth,  Ber.,  1894,  27,  216. 


THE  POLYMETHYLENES  29 

Heptamethylene,  or  suberane,  was  obtained  by  Markowni- 
koff l  from  suberic  acid  (I.)  by  means  of  the  second  general 
method.  The  distillation  of  calcium  suberate  gave  suberone 
(II.),  which  was  reduced  to  suberyl  alcohol  (IIL),  from  which 
suberyl  iodide  (IV.)  was  formed,  which  on  reduction  with  zinc 
and  hydrochloric  acid  gave  suberane  (V.). 

CH2 .  CH2 .  CH2 .  COOH  CH2 .  CH2 .  CH2 

H 

CH2.CH2.CH2COOH  CH2.CH2.CO 

(I.)  (II.) 

CH2.CH2.CH2 


CH 

\ 


>  CH 


>  CH 

\. 


CH2.CH2.CH.OH  CH2.CH2.CH.I  CH2.CH2.CH2 

(IIL)  (IV.)  (V.) 

It  is  a  liquid,  boiling  at  118°  C.  under  a  pressure  of  726  mm. 
and  having  a  peculiar  odour  like  naphtha. 

The  preparation  of  octomethylene  is  much  more  difficult. 
It  has  been  carried  out  by  Willstatter  and  Veraguth  2  in  the 
following  steps.  The  bark  of  the  "pomegranate  tree  contains 
an  alkaloid  pseudo-pelletierine  which  is  a  ring-homologue  of 
tropinone,  and  has  the  constitution  expressed  by  (I.).  This  was 
converted  into  the  N-methyl-granatanine  (II.)  in  which  two 
hydrogen  atoms  replace  the  oxygen  of  the  ketonic  compound. 

CH2 — OH 0x1.2  OH2 — OH OH2 

III  III 

CH2    N— CH8    CO  CH2    N— CH8    CH2 

CH2— CH CH2  CH2— CH CH2 

(I.)  (II.) 

By  exhaustive  methylation,  this  compound  is  converted 
into  des-dimethyl-granatanine  (III.),  the  nitrogen  bridge  being 
broken  in  the  process. 

1  Markownikoff,  /.  Rnss.  Phys.  Chem.  Soc.,  1893,25,364,547;  Willstatter 
and  Kametaka,  Per.,  1908,  41,  14SO. 

2  Willstatter  and  Veraguth,  Ber.,  1905,  38,  1975 ;  1907,  40,  957. 


30      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

N(CH3)3OH 
—  OH 


CH2  CH2 

I  .  I 

Oii2  —  OH  —          OH 

(in.) 

This  substance,  on  distillation,  breaks  down  into  water,  tri- 
methylamine,  and  a  cyclo-octadiene,  CsH12.  This  last  substance 
is  unstable,  and  polymerizes  with  almost  explosive  violence. 
When  hydrobromic  acid  is  allowed  to  react  with  it,  it  forms  a 
dihydrobromide,  C&HuBty,  from  which  hydrobromic  acid  can  be 
removed  by  means  of  quinoline.  The  compound  thus  produced, 
however,  is  not  the  original  cyclo-octadiene,  but  an  isomeric 
and  much  more  stable  body,  The  constitution  of  neither 
compound  has  been  established  with  certainty,  but,  as  will  be 
seen  immediately,  this  does  not  affect  the  present  question. 
When  the  stable  cyclo-octadiene  is  reduced  by  the  Sabatier 
and  Senderens  method  it  produces  a  hydrocarbon,  CsHig, 
boiling  between  147°  and  149°.  This  substance  is  not  an 
olefine,  as  it  is  unattacked  by  permanganate  of  potash  ;  so  that 
it  must  be  a  polymethylene  of  some  sort.  On  oxidation  with 
nitric  acid  it  produces  suberic  acid,  which  proves  that  all  the 
carbon  atoms  lie  in  a  single  straight  chain  — 

CH2  .  CH2  .  CH2  .  CH2  CH2  .  CH2  .  CH2  .  COOH 

I  I  --  >      I 

CH2  .  CH2  .  CH2  .  CH2  CH2  .  CH2  .  CH2  .  COOH 

The  only  possible  conclusion  is  that  the  hydrocarbon  is 
octomethylene.  It  is  a  solid,  melting  at  14'2°  C.  and  boiling  at 
150°  C.  under  709  mm.  pressure. 

The  last  compound  with  which  we  have  to  deal  is  nono- 
rnethylene,  which  was  recently  discovered  by  Zelinsky.1  He 
obtained  it  by  the  second  general  method,  starting  from  sebacic 
acid  (I.),  which,  by  distillation  of  the  calcium  salt,  he  converted 
into  the  corresponding  ketone  (II.),  and  thence,  by  reduction,  to 
the  alcohol  (III.),  which,  by  conversion  into  the  iodide  and 
further  reduction,  gave  nonomethylene  (IV.). 
1  Zelinsky,  Ber.,  1907,  40,  3277. 


THE  POLYMETHYLENES 


GH2 .  GH2 .  Grl2 .  GH2 .  COOH  GH2 .  GH2 .  GtT2 .  GH2 


CH2.CH2.CH2.CH2 
(II.) 


CH2 .  CH2 .  CH2 .  CH2 .  COOH 

(I.) 
CH2 .  CH2 .  CH2 .  CH2 

^CH .  OH       |  ^CH2 

riTT     r*ir     PIT     r<TT  r<ir     PIT    PTT     PIT 

V^X12  .  wXl2  .  L^X12  .  \jii-2  v^JLl2  .  V^-H2  .  \jtt.%  .  v^JLljj 

(III.)  (IV.) 

It  is  a  liquid  of  boiling-point  170°-172°  C. 

We  have  now  given  a  sufficient  account  of  the  methods  by 
which  these  substances  can  be  formed,  and  must  next  take  up 
the  question  of  the  effects  which  the  ring-formation  produces 
upon  the  general  type  of  polymethylenes.  These  saturated 
cyclic  compounds  occupy  a  peculiar  position  in  the  field  of 
organic  chemistry.  Eelated  on  the  one  hand  to  the  aromatic 
series,  from  which  some  of  them  can  be  derived,  they  resemble 
aromatic  bodies  to  some  extent  in  their  stability ;  while  on 
the  other  hand  their  actions  with  certain  reagents  bring  them 
more  into  line  with  the  defines,  whose  isomers  they  are.  In 
stability  they  seem  to  mark  a  transition  stage  between  the 
ordinary  define  and  the  analogous  saturated  paraffin.  In 
physical  properties  also  the  polymethylenes  lie  apart  from 
both  define  and  paraffin  series ;  and  it  may  be  well  to  examine 
this  part  of  the  subject  before  dealing  with  the  chemical 
behaviour  of  the  cyclic  group. 

From  the  point  of  view  of  chemistry  the  boiling  and 
melting  points  of  a  substance  are  two  of  its  most  important 
physical  properties,  as  by  their  aid  we  can  separate  or  identify 
isomeric  compounds.  We  may,  therefore,  begin  by  considering 
the  boiling-points  of  the  olefinic,  polymethylene,  and  paraffin 
derivatives,  comparing  in  each  case  the  three  compounds  which 
have  the  same  number  of  carbon  atoms  in  the  chain — 


Boiling-point  of 

No.  of 

carbon  atoms. 

Olefinc. 

Polymethylene. 

Paraffin. 

3 

-48° 

circa  -  35° 

-45° 

4 

-    5° 

+  12° 

+    1° 

5 

+  40° 

49° 

36° 

6 

69° 

81° 

69° 

7 

95° 

117° 

98° 

8 

122° 

146° 

126° 

9 

— 

171° 

150° 

32      RECENT  ADVANCES   IN   ORGANIC    CHEMISTRY 

Thus  in  every  case  the  boiling-point  of  the  polymethylene 
is  the  highest  of  the  three.  This  emphasizes  the  peculiar  cha- 
racter which  the  ring-formation  confers  upon  substances,  for 
in  most  cases  the  saturated  (paraffin)  compound  has  almost  the 
same  boiling-point  as  the  corresponding  olefinic  derivative. 

In  molecular  volumes  also1  the  polymethylenes  lie  quite 
apart  from  the  olefines  and  paraffins,  as  the  following  table 
shows : — 


No  of 

Molecular  volumes  of 

carbon  atoms 

in  chain. 

Olefine. 

Polymethylene. 

Paraffin. 

4 

89-8 

79-06 

96-5 

5 

104-3 

91-09 

112-4 

6 

119-1 

105-19 

127-2 

7 

136-3 

118-00 

142-5 

8 

151-5 

130-92 

158-6 

9 

~~~ 

159-46 

174-3 

From  this  it  appears  that  the  molecular  structure  of  the 
polymethylenes  is  much  more  compact  than  that  of  the  corre- 
sponding olefines;  and,  further,  the  higher  polymethylenes 
are  relatively  less  voluminous  than  the  lower  members.  For 
example,  the  difference  in  volume  between  the  two  isomeric 
compounds  with  four  carbon  atoms  is  ten  units,  while  that 
between  the  volumes  of  isomeric  compounds  of  eight  carbon 
atoms  is  twenty  units  ;  over  the  same  interval  the  difference 
between  the  olefine  and  corresponding  paraffin  remains  almost 
unaltered — seven  units. 

Briihl2  has  shown  that  ring-formation  has  no  noticeable 
effect  upon  the  molecular  refraction  of  compounds;  thus  the 
difference  between  the  refractive  power  of  a  saturated  paraffin 
and  that  of  the  corresponding  ring  is  to  be  found  merely  by 
subtracting  the  value  of  two  hydrogen  atoms  from  the  larger 
figure,  taking  no  account  of  the  change  in  constitution. 

Stohmann  and  Kleber 3  have  examined  the  question  of  the 
relation  between  ring-formation  and  thermo-chemical  behaviour 
in  an  exhaustive  manner.  In  the  following  table  column  I. 

1  Willstatter  and  Bruce,  Ber.,  1907,  40,  3979,  and  Smiles,  Relation  between 
Chemical  Constitution  and  Physical  Properties,  Chapter  IV. 

2  Briihl,  Ber.,  1892,  25,  1954;  Willstatter  and  Bruce,  Ber.,  1907,  40,  3979. 

3  Stohmann  and  Kleber,  /.  pr.  Ch.,  1892,  II.  45,  489. 


THE  POLYMETHYLENES  33 

shows  the  increase  in  the  heat  of  combustion  when  a  poly- 
methylene ring  is  broken  and  two  hydrogen  atoms  are  added 
on;  column  II.  shows  the  average  loss  of  energy  in  calories 
which  the  polymethylene  system  suffers  by  the  addition  of  two 

hydrogen  atoms : — 

I.  II. 

Trimethylene  ring      .        .        .     31-9  33-1 

Tetramethylene  ring  .        .        .     29'1  39-9 

Pentamethylene  ring          .        .     52-9  16-1 

Hexamethylene  ring  .        .        .    54'7  14 -3 

The  only  point  of  importance  which  can  be  deduced  from  these 
figures  is  the  fact  that  the  penta-  and  hexa-methylene  rings  lose 
much  less  energy  in  opening  up  than  the  tri-  and  tetra-methy- 
lene  ones  do.  We  shall  have  occasion  to  refer  to  this  point 
later  in  the  chapter. 

When  we  come  to  the  chemical  side  of  the  question,  the 
evidence  is  not  nearly  so  complete  as  is  desirable.  A  good 
deal  of  research  has  been  carried  out  on  the  problem  of  the 
stability  of  polymethylenes  in  presence  of  such  agents  as 
halogen  acids,  permanganate,  nitric,  and  sulphuric  acid ;  but 
up  to  the  present  no  one  appears  to  have  done  any  exact 
comparative  experiments  which  would  enable  us  to  consider 
numerical  relations  between  the  different  cases.  We  must, 
therefore,  content  ourselves  for  the  present  with  noting  the 
main  features  of  the  matter. 

Trimethylene  is  comparatively  unstable.  It  is  attacked  by 
the  halogen  acids  and  by  sulphuric  acid,  the  ring  being  opened 
in  each  case.  Potassium  permanganate  acts  on  it  slowly,  which 
distinguishes  it  from  propylene,  the  latter  being  instantly 
oxidized.  Berthelot1  gives  the  following  data  of  comparison 
between  the  olefine  and  polymethylene : — 


Formation. 

Heat  iu  calories  of 
Bromine  addition. 

Sulphuric  acid 
addition. 

Trimethylene 
Propylene   . 

-17-1 
-    9-4 

+  38'5 
4-29-1 

+  25-5 
+  16-7 

From  this  it  appears  that  trimethylene  has  an  energy-con- 
tent eight  calories  greater  than  that  of  propylene. 

1  Berthelot,  C.  R.,  1899,  129,  483. 

D 


34      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

When  we  turn  to  the  next  higher  member  of  the  series, 
tetramethylene,  we  find  that  it  is  more  stable.  It  is  not 
attacked  by  cold  concentrated  hydriodic  acid  or  by  bromine  in 
chloroform  solution.  When  passed  through  a  heated  tube  in 
the  Sabatier  and  Senderens  method  it  requires  a  temperature 
of  about  200°  to  reduce  it  to  butane,1  whereas  trimethylene  is 
changed  to  propylene  at  100° 2  by  passing  it  over  heated  iron. 
These  last  two  data  are  not  quite  comparable,  but  certainly 
point  to  trimethylene  being  less  stable  than  tetramethylene. 

Pentamethylene  is  a  stable  substance,  being  unattacked  by 
hydriodic  acid  even  when  boiling. 

Hexamethylene  appears  to  be  as  stable  as  pentamethylene. 
It  is  attacked  by  chlorine,  but  instead  of  the  ring  being  opened, 
substitution  takes  place. 

The  almost  equal  stability  of  the  penta-  and  hexa-methylene 
systems  is  well  shown  by  a  peculiar  series  of  changes  by  which 
hexamethylene  derivatives  can  be  isomerized  into  pentamethy- 
lene compounds,  and  vice  versa.  Many  such  changes  are  known, 
and  for  the  sake  of  illustration  we  may  quote  one  or  two  here. 

Aschan3  has  shown  that  when  hexamethylene  is  treated 
with  anhydrous  aluminium  chloride  it  is  converted  below  100° 
into  methyl-pentamethylene.  The  change  appears  to  be  a  purely 
desmotropic  one,  for  no  discoloration  of  the  liquid  was  observed, 
nor  were  any  bye-products  of  condensation  found,  such  as  were 
to  be  expected  if  the  hexamethylene  ring  had  been  broken. 
Perkin  and  Yates  *  found  that  when  camphoric  anhydride  was 
treated  with  aluminium  chloride,  hexahydro-xylylic  acid  was 
formed — 

COOH  CH3        H 

\/ 
C 


CH 


OH  —  O 
CH—  COOH 


1  Willstatter  and  Bruce,  Per.,  1907,  40,  3979. 

2  Ipatjeff,  Ber.,  1902,  35,  1063. 


3  Aschan.  Annale-n,  1902,  324,  11. 

4  Perkin  and  Yates,  Trans.  Ghent.  Soc.,  1900,  79,  1373  ;  Lees  and  Perkin, 
ibid.,  1901,  79,  332. 


THE  POLYMETHYLENES  35 

This  tends  to  show  that  the  five-  and  six-membered  rings  are 
of  almost  equal  stability. 

The  ring  in  the  next  homologue  of  the  series,  heptamethy- 
lene,  is  less  stable  than  either  the  five-  or  six-membered 
substances.  Markownikoff  *  has  observed  that  when  iodo- 
heptamethylene  is  heated  with  hydriodic  acid  to  250°  it  is 
converted  into  methyl-hexamethylene  and  dimethyl-pen  ta- 
methylene — 


CH.CHs  CH.CH3 

7          XCH  HCXNCH  HCXXCH 

r^TT       rim  TI  o         riTT  IT  r*          i 

UHo OXlo  -H-oV  v^-H.2  tl<Aj ( 


H2C — CH2 — CH2  H2C        CHg  tl^C CH .  CHs 

CH2 

With  regard  to  the  behaviour  of  octomethylene  and  nono- 
methylene,  the  experimental  data  at  our  disposal  are  too  scanty 
to  allow  of  any  but  very  general  conclusions  being  drawn  with 
regard  to  their  stability.  It  appears  that  they  are  less  stable 
than  the  five-  and  six-membered  rings,  but  no  exact  measure- 
ments have  been  made. 

Enough  has  now  been  said  to  prove  that  the  polymethylenes 
show  somewhat  peculiar  relations  between  their  stabilities  and 
the  number  of  carbon  atoms  in  the  ring.  The  five-  and  six- 
membered  rings  are  the  most  stable,  and  the  stability  decreases 
from  this  maximum,  whether  the  number  of  carbon  atoms  in 
the  ring  be  increased  or  diminished.  Thus,  if  we  take  tri- 
methylene  and  increase  the  size  of  the  ring  by  a  methylene 
group,  we  obtain  the  more  stable  tetramethylene ;  a  further 
introduction  of  a  methylene  group  yields  a  further  increase  in 
stability,  pentamethylene  being  formed.  The  next  methylene 
group,  leading  to  hexamethylene,  hardly  affects  the  stability; 
but  any  further  inclusion  of  methylene  radicals,  instead  of 
increasing  the  stability  as  before,  tends  now  in  the  opposite 
direction,  hepta-,  octo-,  and  nonomethylene  being  each  in  turn 
less  stable  than  its  lower  homologue. 

Taking  this   into  account,  Baeyer2  put   forward  what   is 

1  Markownikoff,  Ber.,  1897,  30,  1214. 

2  Baeyer,  Ber.,  1885,  18,  2277. 


36      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

generally  known  as  his  "  Strain  Theory,"  which  may  be  formu- 
lated as  follows  :  — 

"  The  four  valencies  of  a  carbon  atom  act  parallel  to  the  lines  joining  the 
corners  of  a  regular  tetrahedron  to  its  centre,  making  an  angle  of  109°  28' 
with  each  other.  The  direction  of  the  valencies  can  be  altered,  but  any 
such  alteration  produces  a  strain  whose  amount  is  proportional  to  the  angle 
through  which  the  valencies  are  diverted.'1 

On  Baeyer's  view,  the  state  of  strain  in  the  ring  is  a 
measure  of  the  ring's  stability  ;  the  greater  the  strain  the  less 
stable  the  ring  is  likely  to  be.  We  must  now  apply  this  theory 
to  the  seven  polymethylenes,  and  see  how  far  it  agrees  with 
experimental  results. 

In  trimethylene  the  centres  of  three  carbon  atoms  will  lie 
at  the  corners  of  an  equilateral  triangle,  so  that  the  valencies 
joining  these  carbon  atoms  to  each  other  will  make  an  angle 
of  60°  with  each  other.  But  in  the  original  state  of  things 
these  valencies  were  supposed  by  Baeyer  to  be  inclined  to 
each  other  at  an  angle  of  109°  28'  ;  so  that  two  of  the  valencies 
of  any  carbon  atom  have  been  diverted  through  an  angle  of 
(109°  28'  -  60°),  and  each  valency  has  been  diverted  through 
half  this  angle,  viz.  24°  44'.  Similarly,  in  the  case  of  a  tetra- 
methylene  ring,  the  four  carbon  atoms  lie  at  the  corners  of 
a  square,  and  the  valencies  will  make  an  angle  of  90°  with 
each  other.  Thus,  each  pair  of  valencies  has  been  diverted 
through  an  angle  of  (109°  28'  -  90°),  and  each  single  valency 
has  been  turned  through  half  this  angle,  viz.  9°  44'.  The 
general  formula  giving  the  deviation  for  a  ring-compound 
containing  n  carbon  atoms  is  — 


n 


Applying  this  to  the  seven  polymethylenes,  we  obtain  the 
following  values  for  the  deviation  in  each  case  :  — 

Angle  of  deviation. 
(Ethylene)  .        »  ,    v  .        54°  44' 


Trimethylene 

Tetramethylene 

Pentamethylene 

Hexamethylene 

Heptamethylene 

Octomethylene 

Nonomethylene 


24°  44' 
9°  44' 
0°44' 

-  5°  16' 

-  9°  33' 

-  12°  46' 

-  15°  16' 


THE  POLYMETHYLENES  37 

These  results  are  in  moderate  agreement  with  the  actual 
relations  between  the  stabilities  of  the  polymethylenes.  The 
positive  deviations  are  more  in  accordance  with  experimental 
results  than  the  negative  ones.  Of  course  it  must  be  under- 
stood that  in  no  case  could  the  Strain  Theory  pretend  to 
exactitude,  since  it  assumes  that  the  four  valencies  in  the 
grouping— 

H       0 

v  •    . 

/\ 
H       C 

are  evenly  distributed  in  space,  which  is  most  unlikely. 
Apart  from  this,  however,  the  agreement  between  the  theory 
and  the  facts  is  noteworthy ;  and  it  is  very  desirable  that  we 
should  have  more  exact  data  at  our  disposal  with  regard  to 
the  stability  relations  of  these  compounds,  in  order  to  discover, 
if  possible,  what  the  Strain  Theory  actually  corresponds  to  in 
physico-chemical  relations.1 

We  have  now  completed  our  survey  of  the  polymethylenes, 
and  in  the  next  chapter  we  shall  examine  the  derivatives  of 
the  simple  ring  compounds  which  occur  among  the  terpenes. 

1  Compare  Smiles,  Relations  between   Chemical   Constitution  and  Physical 
Properties,  1910,  pp.  268  et  eeq. 


CHAPTER  III 

THE   MONO-CYCLIC   TERPENES 

1.  Introductory 

WHEN  the  saps  and  tissues  of  certain  plants  (such  as  pines, 
camphor,  lemons,  and  thyme)  are  distilled,  the  distillates  are 
found  to  contain  among  other  things  a  mixture  of  substances 
which  are  classed  under  the  general  head  of  ethereal  oils.  For 
the  most  part  these  ethereal  oils  contain  unsaturated  hydro- 
carbons of  the  general  formula  (CgHs),,  (or  derivatives  of  these 
substances),  and  these  may  be  divided  into  three  classes — 

1.  Open-chain  olefinic  compounds. 

2.  Mono-cyclic  hydrocarbons  (reduced  benzene  derivatives). 

3.  Cyclic  compounds  containing  more  than  one  ring. 

In  the  following  chapters  we  shall  consider  the  first  and 
third  of  these  classes,  while  the  present  chapter  will  be  devoted 
to  the  mono-cyclic  substances. 

In  the  naturally  occurring  compounds  it  is  found  that 
by  far  the  greater  number  of  these  hydrocarbons  have  the 
empirical  formula  CioHi6 ;  and  it  is  not  without  interest  that 
Collie,1  in  polymerizing  ethylene  by  means  of  the  silent  electric 
discharge,  found  that  the  major  part  of  the  substance  used  was 
converted  into  compounds  containing  either  ten  or  fifteen 
carbon  atoms. 

The  nomenclature  of  these  substances  is  at  present  some- 

C 

what  in  confusion.  It  has  been  customary  to  apply  the  name 
terpene  to  any  compound  having  the  composition  C5Hs,  or  any 
polymeric  variety  of  this  type.  This  general  type  was  then 
divided  into  two  others  :  the  "  true  terpenes,"  cyclic  substances 
of  the  formula  Ci0Hi6 ;  and  the  "  olefinic  terpenes/'  which 
are  open- chain  bodies  having  the  formulse  CsHs  and  CioHio. 
Another  system  of  nomenclature  classes  the  whole  group  under 

1  Collie,  Tram.  Ghem.  Soc.,  1905,  87, 1540. 


THE  MONO-CYCLIC   TERPENES  39 

three  heads :  hemi-terpenes,  C5H8 ;  terpenes,  Cl0Hi6 ;  and  sesqui- 
terpenes,  C15H24.  It  will  best  serve  our  purpose  to  divide  the 
terpenes  into  the  three  classes  which  we  mentioned  first,  viz. 
olefinic  terpenes,  mono-cyclic  terpenes,  and  dicyclic  terpenes. 
The  naturally  occurring  mono-cyclic  terpenes  are  for  the  most 
part  derived  from  either  m-  or  ^>-hexahydrocymene. 

Most  of  the  terpenes  are  colourless,  pleasant-smelling  liquids 
of  high  refractive  power.  They  boil  without  decomposition, 
and  are  volatile  in  steam.  Some  are  optically  active,  some 
inactive  by  racemization,  while  others,  containing  no  asymmetric 
carbon  atom,  cannot  show  activity  at  all.  It  is  not  necessary 
to  deal  with  their  chemical  properties  at  present,  as  these  will 
be  brought  out  in  the  following  pages  when  the  constitutions 
of  the  compounds  are  described. 


2.  The  Synthesis  of  Terpineol. 

In  the  group  of  the  mono-cyclic  terpenes,  by  far  the  most 
important  compound  is  terpineol,  for  from  it  most  of  the 
other  members  of  the  group  can  be  prepared,  either  directly 
or  indirectly.  The  constitution  of  terpineol,  therefore,  is  of 
considerable  value  to  us  in  determining  the  constitutions  of 
other  substances  which  we  can  derive  from  it.  The  inactive 
form  of  terpineol  has  been  synthesized  by  Perkin,1  and  as  this 
synthesis  determines  the  constitution  of  the  substance,  we  may 
describe  it  step  by  step. 

When  /3-iodo-propionic  ester  was  allowed  to  interact  with 
the  disodium  derivative  of  cyan-acetic  ester,  -y-cyano-pentane- 
ayt-tricarboxylic  ester  was  produced — 

ON          EtOOC.CH2.CH2    ON 
2EtOOC.CH2.CH2 1  +  Na2C  =  2NaI  +  G 

COOEt    EtOOO.CH2CH2    COOEt 

From  this  the  free  acid  was  obtained  by  hydrolysis  with 
hydrochloric  acid,  and  when  it  was  boiled  with  acetic 
anhydride  and  then  distilled  it  was  transformed  by  loss  of 
water  and  carbon  dioxide  into  S-keto-hexahydrobenzoic  acid — 

1  Perkin,  Trans.  CJirm.  Soc.,  1904,  85,  654, 


40      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 
HOOC .  CH2 .  CH2 

CH .  COOH  =  H20  +  C02  + 

HOOC.CH2.CH2 

CH2.CH2 

+  CO  CH.COOH 

CH2 .  CH2 

»• 

Grignard's  reaction  was  then  applied  to  the  ester  of  this  acid, 
magnesium  methyl  iodide  being  allowed  to  react  with  the 
ketonic  group,  and  in  this  way  S-hydroxy-hexahydrotoluic 
ester  was  formed — 

CH3  CH2.CH2 

\                /             \ 
Mg  +  00  CH .  COOEt > 

/  \  / 

I  CH2.CH2 

CH3    CH2.CH2 

\                        H2o 
>          0  CH.  COOEt > 

/  \  / 

IMgO    CH2.CH2 

CH3    CH2 .  CH2 
H20  \  /   '         \ 

>  C  CH.  COOEt 


.CHo 


HO     CH2.CH2 

When,  by  the  action  of  fuming  hydrobromic  acid,  we  replace 
the  hydroxyl  group  in  this  acid  by  a  bromine  atom  and 
then  remove  hydrobromic  acid  from  the  compound  by  means 
of  weak  alkalis  or  pyridine,  we  obtain  A3-tetrahydro-j9-toluic 
acid — 

CH3       CH2.CH2 

C  CH.  COOEt > 

HO        CH2.CH2 


THE  MONO-CYCLIC   TERPENES  41 


HBr  \ 

--  >  C  OH  .  COOH 


\ 
CH2 . 


Br      CH2 .  CH2 

CH3  .        . 

Alkalis  \  /  \ 

>  0  CH.COOH 

V     C/ 

Oxl  .   U±±2 

After  esterifying  the  acid,  the  Grignard  reaction  can  be  again 
employed,  with  the  result  that  the  ester  group  is  attacked,  and 
on  treatment  with  water  the  intermediate  compound  breaks 
down  into  inactive  terpineol. 

CH2.CH2  CH2.CH2  CH3 

/  \  CHg.Mg.I  /  / 

CH3.C  CH.COOEt >     CH3.C  .CH-C-OH 


4 


CH .  CH2  OH .  CH2  CH3 

Terpineol. 

If  this  synthesis  be  examined  step  by  step  it  will  be  seen 
that  there  can  be  no  doubt  as  to  the  constitution  of  terpineol, 
for  the  reactions  can  only  be  supposed  to  take  place  in  the  way 
shown.  Any  alternative  formulation  of  any  of  the  reactions 
would  at  once  lead  to  contradiction  in  the  later  experiments. 

An  optically  active  terpineol  has  been  prepared  by  Fisher 
and  Perkin 1  by  resolving  the  intermediate  acid  into  dextro  and 
Isevo  forms  before  continuing  the  synthesis. 

3.  The  Decomposition  Products  of  Terpineol. 

The  oxidation  of  terpineol  takes  place  in  several  steps  and 
produces  some  compounds  of  importance  in  the  study  of 
terpene  constitutions ;  we  may,  therefore,  deal  with  the  matter 
briefly  in  this  place. 

It  has  been  shown  by  Wagner  2  that  when  a  compound  con- 
taining a  double  bond  is  oxidized  by  means  of  potassium 
permanganate,  the  first  step  in  the  process  is  the  breaking  of 
the  double  bond  and  the  addition  of  a  hydroxyl  group  to  each 
of  the  atoms  between  which  the  double  bond  originally  lay — 

1  Fisher  and  Perkin,  Trans.  Chem.  Soc.,  1908,  93,  1871. 

2  Wagner,  Ber.,  1888,  21,  1230,  3359;  1891,  24,  683. 


42      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

OH 

R— C— R  R— C— R 

||         +  H20  +  0  =         | 
R_C— R  R_C— R 

in 

In  the  case  of  terpineol  this  rule  holds,  and  it  is  found  that  the 
first  oxidation  product 1  obtained  by  the  action  of  permanganate 
upon  terpineol  is  trihydroxy-hexahydrocymene — 


CH3 

1 

CH3 

1 

C 

C—  OH 

/  \ 

/  \ 

CH2        CH 

CH2         CHOH 

CH2        CH2 

>     1               1 

r^TT                 f  ''TT 

vyXi2          v>/jn2 

\     / 

\   / 

CH 

CH 

C.OH 

C.OH 

CH3        CH3 

CH3        CH3 

Terpineol. 

Trihydroxyhexahydrocymene. 

This  substance,  on  further  oxidation,2  is  converted  into  homo- 
terpenylic  methyl  ketone  by  the  rupture  of  the  single  bond 
between  the  two  hydroxyl-bearing  carbon  atoms— 

CH-  CHa 


CH2      COOH  CH2      CO— 

I  I >    I  I 

CH2      CH2  CH2      CH2 

y 

C—OH  C— OH  C 0 

CH3        CH3  CH3        CH3  CH3        CH3 

Trihydroxyhexa-  Intermediate  acid.  Homoterpenylic 

hydrocymene.  methyl  ketone. 

1  Wallach,  Annalen,  1893,  275, 150. 

2  Ibid.;  Ber.,  1895,  28, 1773;  Tiemann  and  Schmidt,  {bid.,  1781. 


THE  MONO-CYCLIC   TERPENES 


43 


As  is  shown  in  the  formulae,  the  first  product  of  the  oxida- 
tion is  a  hydro xy  acid  which  loses  water  at  once  between  its 
carboxyl  and  hydroxyl  groups,  yielding  the  keto-lactone. 
This  keto-lactone  is  the  first  product  which  can  be  isolated 
when  terpineol  is  oxidized  with  chromic  acid,  for  the  action  is 
so  violent  that  the  trihydroxyhexahydrocymene  is  destroyed 
as  soon  as  it  is  formed. 

Further  oxidation  with  potassium  permanganate l  converts 
the  keto-lactone  into  a  mixture  of  acetic  and  terpenylic  acids — 


CH3 

io 

H2C        CO— 


H9C 


OIL 


OH 

C— 


CH3 
CO.  OH 

COOH   CO— 

I   .          I 
CH2       CH2 

v 


-0 


C 


0 


CH3 

Homoterpenylic  methyl  ketone. 


CH3 


.       CH8 
Terpenylic  acid. 


The  latter  substance,  by  the  action  of  a  five  per  cent,  solution 
of  permanganate,  is  still  further  decomposed  into  terebic  acid — 


COOH      CO- 

I  |, 

CH2          CH2 

"CH 


COOH 

\     „ 
CH 


CO— 

! 

OH2 


-0 


C 


-0 


CH3 

Terpenylic  acid. 


CHa 


Terebic  acid. 


It  will  be  seen  that  these  formulae  for  homoterpenylic, 
terpenylic,  and  terebic  acid  illustrate  the  decomposition  of 
terpineol  quite  satisfactorily.  Any  doubt  as  to  their  accuracy 
was  removed  by  the  synthesis  of  the  three  acids,  which  was 


1  Wallach,  Ber.,  1895,  28,  1776. 


44      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 


carried  out  by  Simonsen.1  Terebic  2  and  terpenylic  acid  3  had 
previously  been  synthesized  in  different  ways.  The  Siinonsen 
syntheses  depend  on  the  application  of  Grignard's  reaction  to 
various  ketonic  esters.  From  magnesium  methyl  iodide  and 
acetyl-succinic  ester  he  obtained  terebic  ester — 


COOEt 
COOEt      CH2 

"CH 


COOEt 


COOEt 


i 


CH3    CH3 

Terebic  ester. 


o 

CH3 

Acetyl-succinic  ester. 

In  exactly  the  same  way  /3-acetyl-glutaric  ester  is  converted 
into  terpenylic  ester,  and  [3-acetyl-adipic  ester  into  homo- 
terpenylic  ester. 

The  constitution  of  terpineol,  then,  may  be  considered  to  be 
completely  established,  both  synthesis  and  degradation  products 
agreeing  with  the  theory. 

4.  The  Constitution  of  Dipentene. 

When  terpineol  is  heated  with  acid  potassium  sulphate  it 
loses  a  molecule  of  water,  and  is  converted  into  dipentene.  It 
is  evident  that  we  may  represent  this  elimination  of  water  in 
either  of  two  ways — 

CH3  CH3  CH3 

;  i      .  '      A          .'.•:  A 


CH 


HC        CH 


H2C        CH 


H2 


C 


v 


C 


C.OH 


CH 


CH, 


CH3        CH3 

(I.)  Terpineol. 

Simonsen,  Trans.  Chem.  Soc.,  1907, 91, 184. 


'H.q 


C 


3        CH2 

(II.) 

Blaise,  C.  R.,  1898, 126,  349. 


Lawrence,  Trans.  Chem.  Soc.,  1899,  75,  531. 


THE   MONO-CYCLIC   TERPENES  45 

Now,  dipentene  can  be  obtained  by  mixing  together  equal 
quantities  of  dextro-  and  Isevo-limonene.  It  is,  therefore,  the 
racemic  form  of  limonene,  and  must  contain  an  asymmetric 
carbon  atom.  Formula  (I.)  contains  no  such  carbon  atom, 
but  the  atom  in  (II.),  which  is  marked  with  an  asterisk,  is 
asymmetric.  Dipentene,  then,  must  have  the  constitution 
represented  by  (II.). 

In  order  to  satisfy  ourselves  that  this  formula  is  the 
correct  one,  we  may  test  it  by  seeing  how  far  it  agrees 
with  some  decompositions  which  dipentene  can  be  made  to 
undergo. 

When  nitrosyl  chloride  is  allowed  to  act  upon  a  compound 
containing  a  double  bond  it  may  unite  with  it  in  either  of  two 
ways.1  If  the  double  bond  lies  between  two  tertiary  carbon 
atoms,  the  chlorine  atom  attaches  itself  to  the  one  and  the 
nitroso-group  to  the  other,  and  the  resulting  substance  is  a  blue 
nitroso-derivative  — 


C=C  NOCI  C--C 

CHs  CH3  CHg 

NO     01 

On  the  other  hand,  if  one  of  the  carbon  atoms  is  a  tertiary  and 
the  other  a  secondary  one,  the  chlorine  of  the  nitrosyl  chloride 
attaches  itself  to  the  tertiary  atom  and  the  nitroso-group  to  the 
secondary  atom.  The  hydrogen  atom  then  wanders,  as  shown 
in  the  formulae  below,  with  the  result  that  a  colourless  iso-mtroso 
compound  is  formed  — 


CH3  CH3  CII 

0=0          NOCI  C—  0  0—0 

/     \  .  --  >      A    ,\ 

CH3  H  CH3!          H  OJ 

01     NO  01    NOH 

We  must  now  apply  this  to  the  case  of  dipentene.     To  make 
reference  easy  we  shall  number  each  step. 

1  Thiele,  Ber.,  1894,  27,  455.. 


46      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 


I.  When  nitrosyl  chloride  acts  upon  dipentene,  it  might  be 
supposed  that  it  could  react  either  with  the  double  bond  in  the 
nucleus  or  with  that  in  the  side-chain.  It  actually  attacks 
the  nuclear  double  bond,  as  we  shall  show  later,  and  to  avoid  the 
complication  of  two  sets  of  formulae  we  may  confine  ourselves 
to  the  case  of  the  addition  to  the  double  bond  of  the  nucleus. 
The  reaction,  if  our  formula  for  dipentene  be  correct,  will  take 
the  course  shown  below  — 


CH 


CH3 
I 


C  C_C1 

/\  /\ 

H2C       CH     NOCI   H2C       CH:NO 

I         I >       I         I 

H2C       CH2  HoC 


CH 


A 

CH3      CH< 

Dipeotene. 


C 


\ 


CH3 

C— Cl 

H2C       C  :  NOH 

I         I 
H2C       CH2 

\/ 
CH 

C 


CH 


H 


CH3       CH2 


II.  When  the  nitrosochloride  formed  in  the  last  reaction  is 
treated  with  alcoholic  potash  it  loses  one  molecule  of  hydro- 
chloric acid,  and  is  transformed  into  a  compound  which  proves 
to  be  identical  with  the  oxime  of  the  ketone  carvone.  This  can 
be  expressed  as  follows  :  — 


CH3 

C— Cl 

/\ 

H2C       C :  NOH 
H2C       CH2 


CH 

C 


HCX    C :  NOH 

H2C       CH2 


CH2 

Dipentene  nitrosochloride. 


C 

/\ 

CH3      CH2 
Carvoxime. 


THE  MONO-CYCLIC   TERPENES  47 

III.  By  hydrolysis  of  the  oxime,  carvone  is  produced. 

IV.  Carvone,   on  reduction,   gives  dihydro-carveol.      This 
reduction  might  be  supposed  to  take  place  either  in  the  nucleus 
or  in  the  side-chain.     As  will  be  shown  later  (VI.),  the  nucleus 
is  reduced  and  the  side-chain  left  untouched.     We  need  not 
concern  ourselves  with  the  alternative  set  of  formulae,  but  may 
again  confine  ourselves  to  the  one  set. 


CH3 

I  I 

C  CH 

HC        CO  H2C      CH.OH 

|          |  >  I 

HP            PTT  TI  C* 

v\j            v^llo  xlavy 


i  i 


Carvone.  Dihydrocarveol. 

V.  On  oxidation,  dihydrocarveol  gives  a  trihydroxy-hexa- 
hydrocymene — 

CH3 

in 

H2C  CH.OH 

H2C  CH3 


C— OH 
CH3        CH2OH 

VI.  On  further  oxidation  a  ketone  alcohol  is  formed — 


48      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

CH3 

CH 

H2C  CH .  OH 

H2C  CH2 


CH 

I 
CO 


CH, 


The  production  of  this  substance  proves  what  was  previously 
stated  in  I.  and  IV.,  viz.  that  the  nitrosyl  chloride  attacks 
the  nucleus,  and  that  in  the  reduction  to  dihydrocarveol  the 
side-chain  double  bond  is  not  reduced.  If  the  nitrosyl  chloride 
had  attacked  the  side-chain  we  should,  at  Stage  III.,  have 
produced  an  aldehyde  of  the  type — 

CH3 

C 

H2C         CH 

i  I 

H2C         CH2 

\/ 

CH 


f\ 

CH2        CHO 

instead  of  the  ketone  produced  in  practice.  If  the  side -chain 
had  been  reduced  in  Stage  IV.  instead  of  the  nucleus,  the 
nucleus  would  have  been  attacked  by  the  oxidizing  agent  in 
Stage  V.,  the  ring  would  have  been  broken,  and  a  ketonic  acid 
would  have  been  formed,  just  as  in  the  case  of  the  oxidation  of 
terpineol. 

VII.  Further  oxidation  of  the  ketonic  alcohol  produced  in 
Stage  VI.  yields  a  hydroxy-acid,  which,  by  the  action  of 
bromine  at  190°  C.,  loses  six  hydrogen  atoms,  and  is  converted 
into  hydroxy-p-toluic  acid — 


THE  MONO-CYCLIC   TERPENES                      49 

£ 

IH 

CH, 

H2C          CH.OH 

Hatf 

CH.OH 

S\ 

HC        COH 

i            i 

'  H2C 

i 

HC        CH 

H2C          CH2 

CH2 

\<            V 

Oxl                                           CM 

V 

CO  COOH  C 


OOH 


CH3 


To  sum  up  the  matter,  we  may  point  out  that  the  series 
of  reactions  IV.  to  VII.  prove  that  the  "isopropyl  group" 
contains  a  double  bond,  which  must  also  be  present  in  dipentene. 
Moreover,  since  this  double  bond  has  persisted  throughout  the 
whole  series  of  reactions  I.  to  IV.,  it  cannot  have  been  the  point 
at  which  the  nitrosyl  chloride  attached  itself,  as  this  portion 
of  the  molecule  has  given  rise  to  the  — CH .  OH —  group. 
Further,  the  nitroso-group  must  have  attached  itself  to  the 
carbon  atom  to  which  the  hydroxyl  group  is  attached  in  the 
aromatic  acid,  i.e.  the  one  next  that  which  carries  the  methyl 
group.  These  reactions  can  only  be  explained  by  assuming  that 
dipentene  has  the  structure  which  we  attributed  to  it  on  account 
of  its  synthesis  from  terpineol. 

It  might  be  objected  that  we  have  not  taken  into  account 
the  possibility  that,  in  the  formation  of  dipentene,  the  elimi- 
nation of  water  from  terpineol  may  take  place  between  two 
non-adjacent  carbon  atoms,  giving  rise  to  some  such  compound 

CH 


50      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

Any  attempt  to  explain  the  question  on  these  lines  leads, 
however,  to  impossible  results,  and  it  may  be  taken  as  proved 
beyond  doubt  by  the  above  Q  jj 

experimental  data  that  the  | 

formula  of  dipentene  is —  C 

H2C        CH 


H2C 

\/ 
CH 


C 


CHS 


Dipentene. 

This,  in  turn,  proves  the  formulae  of  dextro-  and  laevo-limonene, 
for  as  they  are  the  optical  antipodes  of  which  dipentene  is  the 
racemic  variety,  they  also  must  possess  the  same  structural 
formula  as  dipentene. 

5.  The  Constitutions  of  Terpinolene  and  Terpinene. 
In  the  last  section  it  was  pointed  out  that  the  dehydration 
of  terpineol  might  follow  either  of  two  courses  :  the  one  leading 
to  a  compound  containing  an  asymmetric  carbon  atom,  the  other 
to  a  symmetrical  derivative.  The  result  of  dehydration  by 
means  of  acid  potassium  sulphate  was  shown  to  be  dipentene  ; 
but  when  terpineol  is  dehydrated1  by  means  of  alcoholic 
sulphuric  acid,  an  QH3 

isomeric  compound  is  J 

formed    which     has 

the  second  of  the  two  /     OH 

possible  formulae  —  , 

HgC  CHg 

^  2S  A       1 

Cos      CH/j 
This  substance  is  terpinolene. 

Now,  according  to  Thiele,2  the  grouping  (I.)  is  less  stable 

1  Wallach,  Ber.,  1879,  12,  1022.          2  Thiele,  Annalen,  1899,  306,  119. 


THE  MONO-CYCLIC   TERPENES  51 

than  the  grouping  (II.)  in  which  the  two  double  bonds  are 
"  conjugated  "  — 

EREEE  EEEEE 

I       I       I       I       I  I       I       I       I       I 

C  =  C—  C—  C  =  C  E—  C—  C  =  C—  C  =  C 

III  I  I 

E  E  E  E  E 

(I-)  (II.) 

We  need  not  enter  into  the  matter  in  detail  here,  as  it  will  be 
dealt  with  fully  in  a  later  chapter.  For  the  present  it  is 
sufficient  to  apply  Thiele's  view  to  the  behaviour  of  terpinolene. 
This  substance,  on  treatment  with  acids,  can  be  converted  into 
terpinene,  while  terpinene  itself  cannot  be  isomerized  at  all, 
and  is,  in  fact,  the  most  stable  of  all  the  terpene  class.  Since 
the  grouping  (I.)  exists  in  terpinolene,  we  may  conclude  that  it 
is  converted  by  acids  into  the  more  stable  grouping  (II.)  — 

CH3  CH3 


x 

H2C        CH  HC        CH 


.HO  Clr 


C  C 

II  I 

C  CH 

CH3      CH3  CH3       CH3 

Terpinolene.  Terpinene. 

This,  however,  is  only  a  possibility  and  not  a  certainty,  for  the 
alternative  formula 
of  terpinene — 


| 

2C 
HC        C 


H2C        CH 
H2 


v 

I 
CH 

CHa  CH 


52      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

represents  some  properties  of  the  substance  better,  though  it 
does  not  explain  its  stability  so  well.  The  matter  is  still  under 
discussion,  and  need  not  be  dealt  with  further  in  this  place. 

6.  Terpin  and  Cineol. 

Grignard  *  and  others  have  shown  that  when  the  esters  of 
organic  acids  react  with  organo-magnesium  compounds,  tertiary 
alcohols  can  be  produced —  R 

2E.Mg.I  +  E'.COOEt  =  E'.C— OMg.  I  +  EtO.Mg.I 

E 
K  E 


E' .  C— 0  .  Mg .  I  +  H20  =  E' .  C— OH  +  HO .  Mg .  I 

E  E 

Again,  when  ketones  are  treated  with  Grignard's  reagent,2 
tertiary  alcohols  are  formed — 

E  E  E 


R'.Mg.I  H20 

CO >    E'— C— 0. 


CO >    E'—C— O.Mg.I >    E'— C— OH 

E  E  E 

Kay  and  Perkin 3  have  combined  these  two  reactions  into 
one,  using  a  ketonic  ester,  and  allowing  both  vulnerable  groups 
to  be  attacked  simultaneously.  By  this  means,  from  cyclo- 
hexanone-4-carboxylic  ester,  they  obtained  the  dihydric  alcohol 
terpin.  CHa 

CO  C— OH 

r/\,  /S 

TT   /^1  r^TT  TT   C\  C\~r~T 

±i2^        on2  J120        CH2 

II  II 

H2C        CH2  H2C        CHo 


)OOEt  C— OH 

Cyclohexanone-4-carboxylic  ester.  /  \ 

CH3      CH3 

Terpin. 

Grignard,  C.  R.,  1901,  132,  336.  2  Zelinsky,  Ber.,  1901,  36,  3950. 

3  Kay  and  Perkin,  Trans.  Ghent.  Soc.,  1907,  91,  372. 


THE  MONO-CYCLIC   TERPENES  53 

This  synthesis  proves  the  formula  of  terpin  beyond  any 
dispute. 

Terpin  may  be  also  obtained  by  boiling  terpineol  with  dilute 
sulphuric  acid — 

CH3  CHo 


C— OH 

/^  . /\ . 

-ti2C        Cxi  H2C        CH2 

I            l(                      H.O  |  I 

H2C        CH2 ^          H2C        CH2 


CH  H— C 

!  I 

C— OH  C— OH 

GH3       CH3  CH3      CH3 

Terpineol.  Cis-terpin. 

The  terpin  which  is  obtained  in  either  of  these  ways  is 
called  a's-terpin,  from  the  fact  that  in  its  space  formula  the  two 
hydroxyl  groups  lie  on  the  same  side  of  the  hexamethylene 
ring,  while  in  the  isomeric  compound,  £nms-terpin,  they  lie 
on  opposite  sides  of  the  ring — 


OH  HO—  C(CH3)2          CH3  HO—  C(CH3)2 

CH2  -  CH2,     | 

C 


| 
C 

| 
O 


CH3  H  OH  H 

Cis-terpin.  Trans-terpin. 

Cis-terpin  unites  with  one  molecule  of  water  to  form  terpin 
hydrate,  a  crystalline  substance  from  which  it  can  be  regene- 
rated at  100°  C.  The  trans-isomer  does  not  unite  with  water 
at  all. 

Cis-terpin  cannot  be  directly  converted  into  trans-  terpin, 
but  the  change  can  be  effected  by  a  somewhat  roundabout 
method.  In  the  first  place,  cis-terpin  is  subjected  to  the  action 
of  hydrobromic  acid,  by  which  means  a  dibromide  is  formed. 
As  can  be  seen  from  its  formula,  this  substance  is  identical  with 
the  hydrobromide  of  dipentene  — 


54      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

CH3 
C—  Br 

H2w  OJtlg 

H2C         CH2 

\x 

H—  C 


*    C—  Br 
CH3       CH3 

Dipentene  dihydrobromide 
(Cis-terpin  dibromide). 

This  dibromide  is  next  treated  with  silver  acetate  in  acetic 
acid  solution,  and  the  diacetate  so  produced  is  hydrolyzed  with 
alcoholic  potash,  yielding  tfnms-terpin. 


CH3  OH3 

Br—  C  CHaCO  .  0—  C  C—  OH 

H2C        CH2  H2C        CH2  H.2C        CH2 

I         I  --  >  I          I       --  >        I          I 

H2C        CH2  H2C        CH2  H2C        CH2 

C—  H  G—  H  C—  H 


Br— C  CHgCO  .  00  HO— C 

/\  /\  /\ 

CH3       OH3  CH3        CH3  CH3       OH, 


It  should  be  noted  that  when  cis-terpin  is  converted  into  its 
dibromide  the  product  is  the  cts-form  of  dipentene  dihydrobro- 
mide ;  while,  on  the  other  hand,  the  action  of  hydrobromic  acid 
on  trans-terpin  produces  the  trans- variety  of  dipentene  dihydro- 
bromide. Thus  the  change  of  cis-terpin  into  trans-terpin 
cannot  be  carried  out  through  the  bromides  alone,  as  during 
their  formation  no  change  from  cis-  to  trans-form  takes  place ; 
this  only  occurs  during  the  hydrolysis  of  the  acetyl  derivative. 

When   cis-terpin    is    dehydrated,   it   yields    a   variety   of 


THE  MONO-CYCLIC   TERPENES 


55 


products  (terpineol,  dipentene,  terpinene,  and  terpinolene), 
among  which  is  found  the  compound  cineol,  Ci0H180.  This 
substance  contains  neither  a  hydroxyl  nor  a  carbonyl  radical, 
and  must  therefore  be  an  ether.  On  this  view,  its  formation 
from  cis-terpin  is  easily  explained — 


CH3— C— OH 

/\ 
H2C        CH2 

H2C        CH2 

\/ 

H— 0 

C-OH 
CH3      CH3 


CH3—  C- 

H2C  CH2 

H2C       CH2  0 

\/ 

H— C 


'Hq 


CH3 


This  formula  is  supported  by  the  fact  that  hydrobromic  acid 
in  acetic  acid  solution  converts  cineol  into  cis -dipentene 
dibromide — 


CHa— C- 


H2C        CH2     0 


CH3 


CH3— C— Br 
HC/NCH 

Xi2v>'          V^Jn.2 


H— 

C— Br 
CH3     CH3 


The  behaviour  of  cineol  on  oxidation  with  potassium  per- 
manganate is  curious.1  The  first  effect  is  to  break  the  hexa- 
methylene  ring,  while  leaving  the  ether  chain  untouched ;  in 
this  way  cineolic  acid  is  produced — 


1  Wallaeli  and  Gildemeister,  Annalen,  1888,  246,  268  ;  Wallach,  ibid.,  1890, 
258,  319;  Wallach  and  Elkeles,  ibid.,  1892,  271,  21. 


CH3 
-C 
H2C       CH2 


56      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

CHg 

C 

/\ 

H2C       COOH 
0  H2C        COOH 

¥ 

C 

CH3      CH3 

Cineolic  acid. 


0  H2C      CH2 

v 

OH 


0  O  £ 

Cineol. 


When  cineolic  acid  is  treated  with  acetic  anhydride  it  yields 
cineolic  anhydride,  which,  on  dry  distillation,  breaks  down 
quantitatively  into  carbon  monoxide,  carbon  dioxide,  and 
rnethyl-heptenone,  an  aliphatic  ketone  of  considerable  interest 
from  its  relations  to  the  terpenes — 


CH3 
CO 


CH2 
CH2 


CO 

C02 


CH3      CH3 

Cineolic  anhydride. 


C 

'\ 

)H3    CH3 

Methyl  heptenone. 


7.  The  Synthesis  of  Carvestrene. 

Until  quite  recently,  carvestrene  could  be  obtained  only  by 
a  very  long  and  complicated  series  of  reactions ;  and  the  con- 
stitutions of  some  of  the  intermediate  compounds  produced  had 


THE  MONO-CYCLIC   TERPENES 


57 


not  been  well  established.  Perkin  and  Tattersall1  have  now 
succeeded  in  synthesizing  it  by  a  series  of  reactions  analogous 
to  those  employed  by  Perkin  in  his  synthesis  of  terpineol. 

The  starting-point  of  this  new  synthesis  was  ra-hydroxy- 
benzoic  acid.  This  was  first  reduced  with  sodium  and  alcohol, 
forming  hexahydro-m-hydroxy-benzoic  acid  ;  from  which,  by 
oxidation  with  chromic  acid,  y-keto-hexahydrobenzoic  acid  (I.) 
was  obtained.  The  ester  of  this  acid  reacts  with  magnesium 
methyl  iodide,  giving  the  lactone  of  y-hydroxy-hexahydro-ra- 
toluic  acid  (II.).  When  this  is  heated  with  hydrobromic  acid 
it  yields  -y-bromohexahydro-m-toluic  acid  (III.),  which  on  treat- 
ment with  pyridine  loses  hydrobromic  acid,  and  is  changed 
into  tetrahydro-w-toluic  acid  (IV.).  After  esterification,  this  is 
treated  with  magnesium  methyl  iodide  and  water,  whereby  an 
alcohol  (V.)  is  produced  which  differs  from  terpineol  in  that  the 
hydroxyl  and  methyl  groups  are  in  the  1,  3  position  to  each 
other,  while  in  terpineol  they  are  in  the  1,  4  position.  Just  as 
terpineol,  when  treated  with  acid  potassium  sulphate,  loses 
water  to  form  dipentene,  this  new  alcohol  loses  water  and  forms 
carvestrene  (VI.). 

CH3 


CO 

H  /  XCH 

tt%\j  v^£l2 

H2C        CH .  COOH 


C 


0 


HC 


i 


H.CO 


/ 


(i.) 


(ii.) 


HO7 

JUavy 


CH3 
C— Br 
CHS 


/ 


\ 


CH 


H2C        CH.COOH 

\/ 
CH2 

(III.) 


H2C        CH.COOH 

\/ 

CH2 

(IV.) 


Perkin  and  Tattersall,  Tram.  Chem.  Soe.,  1907,  91,  480. 


58      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 


i  i 


H2C         OH         CH-3  ji2C 

I      i      /  I      I 

H2C        CH.C— OH  H2C        CH.C 

\/         \  \  / 

CH2  CHs  CH2 

(VI.) 


Though  since  the  discovery  of  this  new  synthesis  the  old 
way  of  preparing  carvestrene  has  lost  its  value  as  a  practical 
method,  we  may  give  a  very  brief  description  of  it  here  on 
account  of  one  transition  which  occurs  in  the  course  of  the 
reactions.  The  starting-point  for  the  old  synthesis  was  the 
substance  carvone,  which  we  have  already  encountered.  Now, 
as  can  be  seen  from  the  formulae  of  the  two  substances,  to 
convert  carvone  into  carvestrene  we  must  shift  the  isopropylene 
group  from  one  carbon  atom  to  the  adjacent  one.  How  this  is 
done  will  be  seen  in  due  course. 

CH3 

C  CH3 

HC        CO  C 

H2C        CH2  H2C        CH         CH2 

•\/  I          I         / 

CH  H2C        CH— C 

\x     \ 

r\-rr  OTT 

U±12  ^-tls 

v,  Carvestrene. 

CH2 

Carvone. 

Carvone  is  first  reduced  with  zinc  dust  and  alcoholic  potash 
to  dihydro-carvone ;  hydrobromic  acid  is  then  added  on,  giving 
dihydrocarvone  hydrobromide  * — 

*  When  a  halogen  acid  is  added  on  to  the  double  bond  of  an  unsaturated 
substance,  the  negative  part  (i.e.  the  halogen  atom)  always  unites  with  that  car- 
bon atom  to  which  the  fewest  hydrogen  atoms  are  attached.  For  example,  in  the 


THE  MONO-CYCLIC   TERPENES  59 

CHg 


H2C  CO 

H2C          CH, 


C— Br 

CH3        CH3 

Now,  when  this  substance  is  treated  with  alcoholic  potash  it 
gives  up  hydrobromic  acid,  but  instead  of  regenerating  a  carvone 
derivative  it  yields  a  new  ketone,  carone.  Since  on  oxidation 
carone  yields  1,  l-dimethyl-2,  3-trimethylene  dicarboxylic  acid 
(caronic  acid),  it  must  contain  a  trimethylene  ring.  The 
simplest  way  in  which  this  can  be  explained  is  to  assume  that 
carone  has  either  of  the  formulas  (I.)  and  (II.). 

CHg  CHg 

CH  CH 

/\  /\ 

H2C        CO  H2C        CO 

H20         OH  HO         OH2 

\ 


CH 


CH 


/ 


C  CH8—  C 

CH3  CH3 

ax.) 

case  given  below  the  compound  formed  by  the  addition  of  hydrobromic  acid  to 
(I.)  is  (II.),  and  not  (III.) 

CH,  CH3   Br  CH3 

\  \l  \ 

C  =  CH2  C—  CH3  CH—  CH2Br 

CH3  CH3  CH3 

(i.)  (n.)  (in.) 

This  is  called  the  "  Markownikolf  Eule"  (Her.,  1869,  2,  660;  Annalen,  1870, 
153,  256). 


60      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

The  first  of  these  formulae  is  the  one  usually  ascribed  to 
carone.  We  cannot  enter  into  the  details  of  the  evidence  here. 

When  carone  is  allowed  to  react  with  hydroxylamine  it 
forms  the  substance  carone  oxime,  which,  on  reduction,  produces 
the  amino-compound  carylamine — 


H2C 


CH  CH 

C:NOH  H2C         CH.NH2 


H2C          CH  H2C         CH 

CH C(CH3)2  CH C(CH3)2 

Carone  oxime.  Carylamine. 

When  this  body  is  treated  with  alcoholic  acid  it  undergoes 
isomeric  change,  and  is  converted  into  the  hydrochloride  of 
vestrylamine,  the  trimethylene  ring  being  now  broken.  By 
this  means  we  have  transferred  the  isopropylene  group  from 
one  carbon  atom  to  the  other — 

CH3  CH3 

CH  CH 

H2C          CH.NH2        HCI        H2C          CH.NH2 


CH 

CH C(CH3)2  H2C         CH— C 

Carylamine.  \    / 


CH 


Vestrylamine. 

Vestrylamine  hydrochloride,  on  dry  distillation,  breaks  down 
into  carvestrene  by  loss  of  ammonium  chloride — 

C10H17 .  NH2 .  HCI  =  C10H16  +  NH4C1 

Carvestrene  is  a  racemic  compound,  the  dextro-antipode  of 
which  is  found  in  nature  as  sylvestrene.1  The  latter  has 
recently  been  synthesized  by  Perkin.2 

1  Baeyer,  Ber.,  1894,  27,  3485. 

2  Perkin,  Proc.,  1910,  26,  97. 


THE  MONO-CYCLIC   TERPENES  61 

8.  The  Synthesis  of  Mentkone. 

Though  menthone  had  been  synthesized  in  different  ways 
by  Einhorn  and  Klages,1  Kotz  and  Hesse2  and  Haller  and 
Martine,3  none  of  these  methods  furnished  any  proof  of  the 
constitution  of  the  substance.  It  was  not  until  1907  that 
synthetic  evidence  was  obtained  upon  this  point. 

Kotz  and  Schwarz  4  first  synthesized  /3-methyl-a'-isopropyl- 
pimelic  acid,  and  by  the  distillation  of  its  calcium  salt  they 
produced  menthone — 

CH3  CH3 


CH 

H2C  CH2.COO  H2C  CH2 

I  I'  I  I 

H2C  COO  -  Ca          H2C  CO 


Calcium  £-Methyl-a'-isopropyl-pimelate.  Menthone. 

A  similar  result  is  obtained  by  making  the  ester  of  this 
acid  undergo  intramolecular  acetoacetic  ester  condensation  by 
means  of  sodium,  and  then  hydrolyzing  the  ester  thus  obtained 
and  splitting  off  carbon  dioxide  in  the  usual  way. 

CH3  CH3 

CH  CH 

H2C        CH2.COOEt  H2C        CH.COOEt 

H2C        COOEt  H2C        CO 

v          v 

U 


C3H7 

1  Einhorn  and  Klages,  Ber.,  1901, 34,  3793. 

2  Kotz  and  Hesse,  Annalen,  1905,  342,  306. 

3  Haller  and  Marline,  C.  22.,  1905,  140,  130. 

4  Kotz  and  Schwarz,  Annalen,  1907,  357,  206. 


62      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 


CH-3 

CH  CH 

H2C  CH.COOH        H20  CH 

H2C  CO  H2C  CO 

' 


CeHj  03X17 


By  means  of  this  synthetic  method,  Kotz  and  Schwarz  have 
produced  an  active  menthone  which  is  strongly  dextro-rotatory. 


9.  The  Decompositions  of  Menthone. 

Before  the  discovery  of  the  syntheses  which  we  have  just 
described,  it  had  not  been  possible  to  show  synthetically  that 
the  methyl  and  iso-propyl  radicals  in  menthone  lay  in  the 
para-position  to  each  other.  The  evidence  for  this  had, 
however,  been  obtained  from  the  decomposition  reactions  of 
menthone. 

When  menthone  is  oxidized  by  means  of  potassium  perman- 
ganate, the  first  product  is  hydroxy-menthylic  acid,1  which,  on 
further  oxidation,  is  converted  into  /3-methyl-adipic  acid — 


CH3 

in 

CH8 

•K 

CH3 

H2C          CH2 

H2C          CH2 

/H 

H2C 

CH2 

H2C          CO 

H2C          COOH 

H2C 

COOH 

Xc/ 

V 

COOH 

<U 

C3H7 

Menthone.  Hydroxymenthylic  acid.    j8-Methyl-adipic  acid. 

1  Arth,  Ann.  Chim.  PJtys,,  1886,  VI.,  7,  433;  Beckmann  and  Mehrlauder, 
Annalen,  1896,  289,  367. 


THE  MONO-CYCLIC   TERPENES  63 

These  substances  could  be  formed  only  if  the  isopropyl  and 
methyl  radicals  were  in  the  para-position  to  each  other  ;  for  if 
we  take  them  in  any  other  position,  as  shown  below,  the 
resulting  products  are  not  the  same  — 

CH3  CH3  CH3 

CH  CH  CH 

H2C          CH.C3H7      H2C          CO.C3H7       H2C         COOH 

HC          CO  H2C 


2C          CO  H2C          COOH  H2C         COOH 

CH2 


X  CH2 


Ketoacid.  a-Methyl-adipic  acid. 

Again,  the  action  of  phosphorus  pentachloride  on  menthone 
gives  a  dichloro-tetrahydro-cymene,1  which,  by  successive  treat- 
ment with  bromine  and  quinoline,  produces  a  chlorocymene  2 
of  the  constitution  — 

CH3 

C 

/\ 
HC        CH 

II         I 
HC       C  .  Cl 

v 


10.  The  Syntheses  and  Constitutions  of  Menthol  and  Menthene. 

Menthol  is  the  alcohol  corresponding  to  menthone,  from 
which  it  can  be  prepared  by  reduction.  Since  we  have 
established  that  menthone  is  (I.),  it  is  obvious  that  menthol 
must  be  (II.). 

1  Berkenheim,  Ber.,  1892,  25,  694. 

2  Jttnger  and  Klages,  Ber.,  1896,  29,  314. 


64      RECENT  ADVANCES  IN   ORGANIC  CHEMISTRY 
CH3  CH3 

CH  CH 


•*--*-^-v' 

HoC 


H2C          CH2  H2C          CH2 

I >        I  I 

CO  H2C          CHOH 

/  \     / 

!H 


C3H.j 


17  C3H7 

(I.)  (II.) 

Now,     when     we    dehydrate     menthol,     a     hydrocarbon 
^-menthene,  is  formed.     This  might  be  either  (A.)  or  (B.),  since 
we  can  suppose  that  water  is  removed  in  either  of  two  ways — 
CH3 


CH 

CH 

H2C 

CH2 

H^ 

'    \H 

H2C 

CH 

H2C 

II 

(JH 

C  CH 


C3H, 


17  C3H7 

(A.)  (B.) 

The  decision  between  the  two  formulae  can  be  made  by  the 
aid  of  the  evidence  of  the  oxidation  products  of  menthene.1 
When  the  menthene  obtained  from  menthol  is  oxidized  with 
potassium  permanganate  solution,  the  first  product  is  a  glycol, 
which,  according  to  formula  (A.),  would  have  the  constitution — 

CH3 


H2C         CH2 

I  I 

H2C         CH— OH 

VOH 

C3H7 

1  Wagner,  Per.,  1894,  27,  1639. 


THE  MONO-CYCLIC   TERPENES  65 

Further  oxidation  yields  a  ketone-alcohol,  then  hydroxy- 
menthylic  acid,  and  finally  /3-methyl-adipic  acid — 


CH 


CH 


CH 


I  I       ~ 

H2C          CO 

0—  OH 


Ketone  alcohol. 


H2C          COOH 

V 

C3H, 

Hydroxymenthylic  acid. 


CH3 

in     K 

HC/    XCH 

.n2vy  V>X12 

H2C          COOH 

\ 
COOH 

£-Methyl-adipic  acid. 


This  is  in  agreement  with  the  experimental  results ;  but  if, 
on  the  other  hand,  we  start  from  the  second  possible  formula 
for  menthene,  the  oxidation  products  would  not  be  those  found 
in  practice,  but  would  be  the  compounds  shown  below— 

CH3 

CH 

H/   NCH 

JlgO  b±l 

I        II 
H2C 

y 

C3H7 

Thus  the  constitution  of  menthene  must  be — 

CH3 

CH 

He*          r<tr 
2v^          v_/.ti2 

1       JH 


CH8 

1 

CH3 

1 

in 

CH 

/  \ 

CHOH 

I          

H2C        COOH 
y      i 

CHOH 

H2C         COOH 

i/ 

V 

i 

C3H, 

C3H, 

H2C 


c 


66      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 

This  has  been  confirmed  by  Wallaeh's  recent  synthesis  of 
menthene,1  in  which  he  chooses  as  his  starting-point  1,  4-methyl- 
cyclohexanone  (I.).  This  he  condenses  with  a-bromo-isobutyric 
ester  by  means  of  zinc,  forming  (II.) ;  and  then,  by  hydrolysis 
and  heating,  causes  the  acid  to  lose  carbon  dioxide  and  become 
converted  into  an  alcohol  (III.),  which,  on  boiling  with  sul- 
phuric acid,  loses  water  and  yields  menthene. 


H2C 


CH3  CH 

CH  CH 

'    \  /  N 

CH2  H2C 

0-tlq  HoO 


vy 

(CH3)2C        OH 


COOEt 
(I.)  (II.) 


CH3  CH3 

CH  CH 

H2C        CH2  H2C        CH2 

H2C        CH2  H2C        CH 

\  /  \  * 

C  C 


(CH3)2CH         OH  CH 

CH3         CH£ 
(HI.)  (IV.) 

Menthene. 

1  Wallaoh,  Ser.,  1906,  39,  2504. 


THE  MONO-CYCLIC   TERPENES  67 


11.  The  Constitution  of  Pulegone. 

The  last  compound  of  the  menthone  group  with  which  we 
need  deal  is  the  unsaturated  ketone  pulegone. 

If  a  ketone  contains  a  double  bond  in  the  a]3-position  to  the 
carbonyl  group,  hydroxylamine  may  react  with  it  in  two  ways, 
forming  an  oxime  in  the  one  case,  and  in  the  other  attaching 
itself  to  the  double  bond  to  give  a  hydroxylamine  derivative. 
For  instance,  in  the  case  of  mesityl  oxide,  we  may  have  either 
mesityl  oxime  or  diacetone-hydroxylamine  produced — 

CH3.C:NOH  CH3.CO 

CH  CH2 

II  I 

C  C.NH.OH 

CH3    CH3  CH3    <JH3 

Mesityl  oxime.  Diacetone-hydroxylaraine. 

Now,  since  pulegone  shows  a  similar  behaviour,  forming 
either  an  oxime  or  a  hydroxylamine  derivative,  the  presump- 
tion is  that  it  also  is  a  ketone  with  an  unsaturated  group  in 
the  a/3-position  to  the  carbonyl  radical. 

Again,  pulegone  on  reduction  is  converted  into  menthone 
so  that  it  must  contain  the  skeleton — 


C         C 
C         CO 

\y 


C 


And  since  we  have  found  that  it  has  the  properties  of  an 
unsaturated  ketone  it  can  have  only  three  possible  formulae 


68      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 
CH3  CH3  CH3 

CH  C  CH 

H2C        CH2  H2C        CH  H2C        CH2 

H2C        CO  H2C        CO  HC         CO 

v 


V 


C  CH  CH 

CH3    CH3  CH3    CH3  CH3    CH3 

(A.)  (B.)  (C.) 

The  evidence  which  enables  us  to  choose  between  these 
three  has  been  supplied  by  Wallach,1  who  has  shown  that 
when  pulegone  is  heated  under  pressure  with  water  or  anhy- 
drous formic  acid  it  undergoes  decomposition  into  acetone  and 
methyl-cyclohexanone.  Since  this  reaction  can  be  explained 
by  Formula  A  alone,  it  is  obvious  that  pulegone  must  have 
that  constitution.  The  break-down  may  be  formulated  in  the 
way  indicated  below — 

CH3 


H2C         CH2 

Yields  methyl-cyclohexanone 
H2C         CO 

C  H2 

|l 

C  O          Yields  acetone 


12.  The  Constitutions  of  the  Phellandrenes. 

The  last  hydrocarbon  of  the  monocyclic  class  with  which  we 
need  deal  is  phellandrene,  and  it  we  must  dismiss  as  briefly  as 
possible. 

1  Wallach,  Annalen,  1896,  289,  337. 


THE  MONO-CYCLIC   TERPENES  69 

Until  a  very  short  time  ago,  phellandrene  was  supposed  to 
be  a  simple  substance,  but  in  1903  Semmler,1  from  a  study  of 
its  oxidation  products,  was  able  to  show  that  it  must  be  a 
mixture  of  two  hydrocarbons,  to  which  he  gave  the  names 
"normal  phellandrene"  and  " pseudo-phellandrene"  They  are 
also  referred  to  as  the  a-  and  /3-forms  of  phellandrene  in  some 
papers.  Both  have  recently  been  synthesized,  the  normal  form 
by  Harries  and  Johnson,2  and  the  pseudo-form  by  Kondakow 
and  Schindelmeister.3 

The  synthesis  of  the  normal  form  is  begun  with  the 
substance  A6-menthenone-2,  but  it  may  be  well  to  show  how 
the  constitution  of  this  body  is  proved  before  we  proceed 
to  the  actual  steps  taken  by  Harries  and  Johnson.  When  car- 
vone  is  treated  with  hydrobromic  acid  it  forms  a  hydrobromide, 
which,  on  reduction  with  zinc  dust  and  methyl  alcohol,  gives  the 
required  menthenone.  As  can  be  seen  from  the  formulae  below, 
no  doubt  as  to  the  constitution  of  the  compound  is  possible. 


C 

CH3      CH2  CH3      CH3  CH3      CH< 

Carvone.  Carvone  hydrobromide.          A6-Menthenone  (2). 

When  this  menthenone  (I.)  is  treated  with  phosphorus 
pentachloride,  its  enolic  form  gives  the  substance  (II.),  which, 
on  reduction  with  zinc  dust  and  methyl  alcohol,  gives 
a-phellandrene — 

1  Semmler,  Ber.,  1903,  36,  1749. 

2  Harries  and  Johnson,  Ber.,  1905,  38,  1832. 

3  Kondakow  and  Schindelmeister,  /.  pr.  Ch.,  1905,  II.  72,  193;  1907,  76, 
141. 


70      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 
(I.)  (II.)  (III.) 


i  i 


HC        C  .  OH 

i          ii 

HC        C  .  Cl 

^           I             II              

HC        CH 

^        \          ii 

1          II 
H2C        CH 

H2C        CH 

>                 II 
H2C        CH 

\  / 

\  / 

\  / 

CH 

CH 

CH 

L 

/  \ 

CH 

/  \ 

<!„ 

/   \ 

/'ITT            riTJ 

V^JLls       v^Xls 

/   \ 
CH3     CH3 

CHs^CH, 

Menthenone.  a-Phellandrene. 

Enolic  form. 


The  synthesis  of  the  isomeric  (3-phellandrene  was  actually 
carried  out  by  starting  from  tertiary  menthene,  but  for  the  sake 
of  clearness  we  may  go  back  in  this  case  also  to  carvone.  On 
reduction,  carvone  (I.)  gives  dihydrocarveol  and  then  carvo- 
menthol  (II.).  This  last  substance,  by  loss  of  water,  can  be 
converted  into  tertiary  menthene  (III.).  By  the  action  of 
bromine  upon  this  compound  a  dibromide  (IV.)  is  formed, 
which,  with  alcoholic  potash,  gives  a  hydrocarbon  having  all 
the  chemical  properties  of  /3-phellandrene. 

Carvone.  Carvomenthol.  Menthene. 


C  CH  C 

S  \  /\  /\ 

HC        CO  H2C        CH.OH  H2C        CH 

HoO         0-tLo  .UoG         OHo  JtioO 


CH 


CH 


CH3      CH2  CH3       CH3  CH3      CH8 

(I.)  (II.)  (m.) 


THE  MONO-CYCLIC   TERPENES  7i 

Dibromide.  0-Phellandrene. 

Oil  3  CH2 

I  II 

0—  Br  C 

H2C        CH.Br  H2C        OH 

II  II! 

H2C        CH2  H2C        CH 


i  i 

CH  CH 

CH3        CH8  CH8        CH3 

(IV.)  (V.) 

With  this  substance  we  may  conclude  our  review  of  the 
monocyclic  terpenes  and  turn  in  the  next  chapter  to  those 
compounds  which  contain  two  rings  of  carbon  atoms  united 
together. 


CHAPTER  IV 

THE  DICYCLIC   TERPENES 

A. — THE  CAMPHENE  GROUP 
1.  Syntheses  of  Camphoric  Add 

IN  the  series  of  dicyclic  terpenes  which  we  are  about  to  describe 
there  are  three  important  classes  of  substances.  One  group  is 
derived  from  the  hydrocarbon  camphene,  another  from  pinene, 
and  a  third  from  fenchene.  Of  these  by  far  the  most  important 
is  the  camphene  group,  with  which  we  shall  deal  first.  The 
central  substance  of  this  group  is  the  compound  camphor 
CioHi60  ;  but  in  order  to  prove  the  constitution  of  this  body  it 
will  be  necessary  to  proceed  step  by  step,  and  in  the  first  place 
to  prove  the  constitution  of  camphoric  acid,  which  is  obtained 
from  camphor  by  oxidation. 

Komppa l  and,  later,  Perkin  and  Thorpe 2  have  synthesized 
camphoric  acid.  We  may  deal  with  both  of  these  syntheses, 
beginning  with  the  method  employed  by  Komppa. 

In  this  synthesis,  the  starting  materials  are  oxalic  ester  and 
/3/3-dimethyl-glutaric  ester.  These  are  condensed  together  with 
sodium  ethylate  in  the  usual  way,  producing  diketoapocamphoric 
ester — 

COOEt    H .  CH .  COOEt  CO CH— COOEt 


|  -  2EtOH 


CHo.C.CH 


CHo— C— CH 


COOEt  H .  CH .  COOEt         CO CH— COOEt 

Diketoapocamphoric  ester. 

This  was  then  methylated  by  means  of  sodium  and  methyl 
iodide,  giving  diketocamphoric  ester — 

1  Komppa,  Ber.,  1903,  36,  4332;  Annalen,  1909,  368,  120;  370,  209;  com- 
l»are  Blano  and  Thorpe,  Trans.  Chem.  Soc.,  1910,  97,  836. 

2  Perkin  and  Thorpe,  Trans.  Chem.  Soc.,  1906,  89,  795. 


THE  DICYCLIC   TERPENES  73 

CO—     — CH— COOEt 

c — CH3 

CO C COOEt 

CH3 

It  is  obvious  that,  since  the  formula  is  symmetrical,  it 
makes  no  difference  which  hydrogen  atom  is  replaced  by  the 
methyl  group  ;  the  end-product  in  each  case  is  the  same. 

This  diketo-ester  was  dissolved  in  sodium  carbonate  solu- 
tion and  then  treated  with  sodium  amalgam  in  a  stream  of 
carbon  dioxide ;  by  this  means  the  two  carbonyl  groups  were 
reduced,  and  dihydroxycamphoric  acid  was  formed,  the  ester 
being  hydrolyzed  by  the  alkaline  solution. 

CH(OH) CH COOH 

CH3— C— CH3 
CH(OH) C COOH 


Dihydroxycamphoric  acid. 

On  boiling  this  substance  with  hydriodic  acid  in  presence  of 
red  phosphorus,  it  is  converted  into  dehydrocamphoric  acid, 
which  may  have  either  of  the  constitutions  shown  below— 

CH-.— Q COOH     CH CH— COOH 

|  |       | 

CH3 — C — CH3  CH3 — C — CH3 

CH2-  -C COOH     CH C COOH 

CH3  CH3 

Dehydrocamphoric  acid. 

The  constitution  of  this  acid  is  of  no  importance,  however, 
as  the  next  two  steps  in  the  synthesis  will  yield  the  same  final 
product  from  either  of  the  two  acids  formulated  above.  The 
dehydrocamphoric  acid  is  heated  with  hydrobromic  acid  in 
acetic  acid  solution  to  125°  C.,  whereby  it  is  converted  into  a 
bromo-acid,  which  is  then  reduced  with  zinc  dust  and  acetic 


74      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

acid  to  a  substance  which  is  identical  with  ordinary  racemic 
camphoric  acid  — 


Br.CH 


CH—  COOH 


CH2 


G-H-3  —  0  — 

C 


-  COOH 


Bromo-acid. 


CH2  -  C  -  COOH 

CHs 

Racemic  camphoric  acid. 


It  will  be  seen  at  once  that  the  exact  constitution  of  the 
dehydrocamphoric  acid  is  of  no  great  importance,  as  the  posi- 
tion of  the  bromine  atom  in  the  bromo-acid  does  not  affect  the 
constitution  of  the  final  camphoric  acid. 

The  synthesis  of  Perkin  and  Thorpe  starts  from  tri- 
methyl-1,  2,  2-bromo-l-cyclopentane  carboxylic  ester,  which  is 
shaken  with  a  mixture  of  potassium  cyanide  and  hydrocyanic 
acid  solutions.  The  resulting  substance  is  heated  and  then 
boiled  with  acetic  anhydride,  whereby  racemic  camphoric 
anhydride  is  formed. 


KCN 


CH 


Trimethyl-bromo-cyclopentane  carboxylic  ester.        Camphoric  acid. 

One  peculiarity  of  camphoric  acid  may  be  pointed  out 
here.  An  examination  of  the  formula  shows  that  camphoric 
acid  has  two  asymmetric  carbon  atoms  in  its  ring  —  these  are 
distinguished  by  asterisks  in  the  following  formula  :  — 


CH 


CHS 


CH—  COOH 


C  — 


COOH 


CH, 


THE  DICYCLIC   TERPENES  75 

Now,  when  we  attempt  to  racemize  dextro-camphoric  acid  by 
any  of  the  usual  methods,  it  is  found  that  instead  of  producing 
an  equimolecular  mixture  of  dextro-  and  laivo-camphoric  acids, 
we  obtain  merely  a  mixture  of  dextro-camphoric  acid  with 
a  new  substance,  laevo-'iso-camphoric  acid.  From  this  be- 
haviour of  camphoric  acid  it  is  deduced  that  instead  of  both 
asymmetric  carbon  atoms  in  the  dextro-acid  being  inverted 
(which  would  give  us  the  mirror-image  Isevo-camphoric)  only 
one  is  altered ;  so  that  half  the  molecule  remains  as  it  was. 
The  change  from  ^-camphoric  to  ^-isocamphoric  would  be 
represented  thus — 

CH3  CH3 

CH2 C  CH2 C 


i\ 


(CH3)2:C 


COOH 


H 


\ 


(CH3)2:C 


COOH 
COOH 


CH2  --  C  CH2  -----    -C 


COOH  H 

d-Camphoric  acid.  Z-Isoeamphoric  acid. 


2.     The  Synthesis  of  Camphor. 

From  synthetic  camphoric  acid  we  can  obtain  camphor 
itself  by  the  following  method.  When  camphoric  anhydride 
is  treated  with  sodium  amalgam  it  is  reduced  to  campholide,1 
the  reaction  being  analogous  to  the  production  of  phthalide 
from  phthalic  acid. 


CH 


CH3  CH3 

Camphoric  anhydride.  Campholide. 

1  Haller,  Bull  soc.  cliim.,  1896,  [Hi.]  15,  7,  984 ;  Forster,  Trans.  Chem.  Soc.t 
1896,  69,  36. 


76      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

Campholide,  on  treatment  with  potassium  cyanide,  produces 
a  nitrile-salt,  which,  on  hydrolysis,  gives  homocamphoric  acid l ; 
this  action  is  exactly  like  that  which  produces  homophthalic 
acid  from  phthalide — 

CH2 CH CH2 

CH3— C— CH3     "o 
OHo C CO 


CH3 

Nitrile-salt. 


Campholide. 


CH3  —  C  —  CH3 
CH2  --  C  ---  COOH 

CH3 

Homocamphoric  acid. 

From  this  homocamphoric  acid  it  is  easy  to  produce  camphor 
itself  by  distilling  the  lead  or  calcium  salt  of  the  acid.2 


CH2 CH— CH2 .  COO 

I  I     -  CaC03 

CH3— C— CH3  Ca > 

CH, C COO 


CH 


CH- 


CHc 


CHc 


This  synthesis  confirms   the  camphor   formula  which  was 
put  forward  in  1893  by  Bredt.3 


3.     Borneol,  Camphene,  and  Camphane. 

When  camphor  is  reduced  by  means  of  sodium  and  alcohol 4 
it  yields  a  secondary  alcohol,  borneol,  which  has  the  formula — 

1  Haller  and  Blanc,  C.  R.,  1900, 130,  376. 

2  Haller,  C.  R.,  1896,  122,  446;  Bredt  and  Rosenberg,  Annalen,  1896,  289,  5- 

3  Bredt,  Ber.,  1893,  26,  3047. 

4  Jackson  and  Menckc,  Am.  Chem.  J.,  1883,  5,  270;  Wallach,  Annalen,  1885, 
230,  225. 


THE  Dl CYCLIC   TERPENES  77 


CH.OH 


OHg 

Borneol. 


This  alcohol  occurs  in  dextro-  and  laevo-forms,  either  of 
which  may  be  obtained  at  will  by  reducing  the  corresponding 
dextro-  or  laevo-camphor.  Borneol  is  not  the  only  product  of 
this  reaction,  however,  as  at  the  same  time  a  small  quantity  of 
an  isomeric  isoborneol 1  is  produced,  whose  constitution  is  not 
yet  definitely  proved. 

The  hydroxyl  radical  in  borneol  can  be  replaced  by  a 
halogen  atom  in  the  usual  way,*  and  if  the  bornyl  iodide  thus 
formed  be  reduced  by  means  of  zinc  dust,  acetic  and  hydriodic 
acids,2  a  hydrocarbon  camphane,  is  produced,  which  is  the  root- 
substance  of  the  camphor  series.  It  has  the  formula — 


CHa 

Camphane. 

On  the  other  hand,  when  bornyl  chloride  or  bromide  is 
heated  with  alcoholic  potash  it  is  converted  into  an  unsaturated 
substance  by  the  loss  of  a  molecule  of  a  halogen  acid.3  The 
constitution  of  this  new  hydrocarbon,  camphene,  CioHie,  is  as 
yet  undetermined.  The  simplest  possible  constitution  would 
be  the  one  shown  below ;  but  this  has  been  proved  to  belong  to 
bornylene,4  which  is  produced  by  the  long-continued  action  of 

1  Montgolfier,  C.  R.,  1879,  89,  101 ;  Haller,  C.  R.,  1887,  105,  227. 

*  In  practice,  however,  bornyl  iodide  is  usually  prepared  by  the  action  of 
hydriodic  acid  on  pinene,  as  the  yields  from  borneol  are  very  poor. 

2  Aschan,  Ber.,  1900,  33, 1006. 

3  Riban,  Ann.  Ghim.  Phys.,  1875,  V.  6,  353. 

4  Wagner  and  Brjckner,  £er.,  1900,  33,  2,  21. 


78      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

alcoholic  potash  upon  bornyl  iodide.     This  substance,  bornylene, 
on  oxidation  yields  camphoric  acid,  which  camphene  does  not  do. 


CH3  —  C  —  CH3 

^1TT                 f1                     ( 

^-i-i-2 

JHOH 
^H 

CH3 
Borneol. 
~TT               flH              C 

CH3-C—  CH3 

1 

CH 


CH, 


-CH 


CH 


CFT.I 


CH3 

Bornyl  iodide. 

•CH COOH 


COOH 


Bornylene. 


CH3 

Camphoric  acid. 


The  oxidation  products  of  camphene  are  much  more  compli- 
cated, and  will  require  a  section  to  themselves.  Before  dealing 
with  them,  however,  we  must  take  up  the  question  of  the 
oxidation  of  camphor  itself. 


4.  The,  Decomposition  Products  of  Camphoi\ 

The  most  vulnerable  point  in  the  camphor  molecule  is  the 
carbonyl  group  and  the  adjacent  methylene  radical.  The  ring  at 
this  point  is  so  easily  attacked  that  it  may  be  broken  by  a  simple 
hydrolytic  reaction.  When  camphor  is  heated  with  sodium 
and  xylene  to  a  temperature  of  280°  C.,  the  ring  opens ;  and 
when  the  reaction  mixture  is  poured  into  water,  the  sodium 
salt  of  campholic  acid l  is  formed. 


CHa—  C—  CH3 


CH 


-GH CHc 

I 


CH3 — C — CHs 


CHo 


C COOH 


CHc 


Camphor.  Campholic  acid. 

1  Malin,  Annakn,  1868,  145,  201  ;  Kachler,  ibid.,  1872,  162,  259. 


THE  DICYCLIC   TERPENES 


79 


The  same  acid  has  been  obtained  by  Haller  and  Blanc  1  from 
campholide,  a  method  of  synthesis  which  establishes  the  consti- 
tution of  the  substance  beyond  doubt. 

CO  CH2  CH2Br  CH3 

/     \      +4H  /    \       HBr  /       2H  / 

H14       0  —  ^  C8H14      0   —  >  C8H14    —  >  C8H14 

v 


C8 


CO 


COOH 


COOH 


Camphoric  anhydride.      Campholide. 


Bromocampholic      Campholic 
acid.  acid. 


Now,  when  campholic  acid  is  oxidized  with  nitric  acid,  the 
newly  formed  methyl  group  is  oxidized  to  carboxyl,  and 
camphoric  acid  is  formed. 


CH, 


CH 


CH 


-CIL 


CH 


CHo 


--COOH 


CH2 CH COOH 

CH3-C— CH3 
CH2 C COOH 


CH3  OH3 

Campholic  acid.  Camphoric  acid. 

Further  action  of  nitric  acid  upon  the  latter  substance 
gives  rise  to  camphanic  acid,  which  is  oxidized  in  its  turn  to 
camphoronic  acid — 


^-iA2  —        —  \j±i  —  —  \j\j\jj^.              V^X12  V 

j  uuun 

^"0 

CH3—  C—  CH3      > 

CH3—  C—  CH3  | 

3H2  ( 

3  COOH            < 

M.  < 

CHc 


Camphoric  acid. 


COOH 

CH3— C— CH 


CH3 

Camphanic  acid. 

COOH 


-COOH 

CH3 

Camphoronic  acid. 

1  Haller  and  Blanc,  G.  R.,  1900,  130,  376. 


8o      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 


The  constitution  of  cainphanic  acid 1  is  proved  by  the  fact 
that  it  can  be  obtained  from  bromocamphoric  anhydride  by 
boiling  with  water — 


CH2 C CO 

IN,  \ 

CH3— C— CH3        0 
CH2 C CO 

CH3 

Bromocamphoric  anhydride. 


C COOH 


CH3 

Camphanic  acid. 


The  constitution  of  camphoronic  acid  was  established  by  the 
synthesis  of  Perkin  and  Thorpe.2  These  authors  first  prepared 
/3-hydroxy-trimethyl-glutaric  ester  by  the  action  of  zinc  upon 
a  mixture  of  acetoacetic  ester  and  a-bromo-isobutyric  ester,  or 
upon  a  mixture  of  dimethyl-acetoacetic  ester  and  monobrom- 
acetic  ester — 

(CH3)2C .  Br      CO CH2 

COOE    CH3       COOlN*(CH3)2C C(OH)— CH2 

/COOE  CH3        COOE 

COOE  CH3         COOE  j8-Hydroxytrimethylglutaric  ester. 

By  replacing  the  hydroxyl  group  first  with  chlorine  and  then 
by  cyanogen  they  obtained  the  nitrile-ester  of  camphoronic  acid, 
from  which  the  acid  itself  was  produced  by  hydrolysis — 


(CH3)2C C(CH3)— CH2     (CH3)2 

COOE    CN  COOE 

Camphoronic  nitrile. 


C(CH3)— CH2 

COOH    COOH     COOH 

Camphoronic  acid. 


When  camphoronic  acid  is  heated  to  above  135°  C.,  it  loses 
water  and  is  converted  into  anhydrocamphoronic  acid,  C9Hi205. 

1  Key  her,  "Dissertation,"   Leipzig,   1891;  Bredt,    Ber.,    1894,    21,    2097; 
Lapworth  and  Lenton,  Trans.  Chem.  Soc.,  1902,  81,  17. 

2  Perkin  and  Thorpe,  Trans.  Chem.  Soc,,  1897,  71,  1169, 


THE  DICYCLIC   TERPENES  81 

By  brominating  the  chloride  of  this  acid,  two  isomeric  bromo- 
anhydrocamphoronic  chlorides  are  produced,  one  of  which,  when 
boiled  with  water,  gives  the  lactone  of  an  unstable  hydroxy- 
camphoronic  acid  (camphoranic  acid),  while  the  other  yields 
stable  hydroxycamphoronic  acid.  Camphoranic  acid,  when 
fused  with  potash,  breaks  down  into  oxalic  and  trimethyl- 
succinic  acids.1  These  changes  may  be  expressed  thus  — 

COOH  COOH  COOH   COOH 

CH3—  C  -  CH2        CH3—  C-    -CH 
CHo     --  >  CH3—  C—  CH3 


C— 


4 


COOH  CO O 

Camphoronic  acid.  Campboranic  acid. 

COOH    COOH 
CH3— CH      COOH 
^  CH3 — C — CH3 

COOH 

Trimethylsuccinic  and  oxalic  acids. 

5.  Camphoic  and  Apocamphoric  Acids. 

Camphene  contains  a  double  bond,  by  means  of  which  it 
unites  with  halogen  acids.  When  it  is  oxidized  by  means  of 
dilute  potassium  permanganate,  the  usual  addition  of  hydroxyl 
groups  at  each  end  of  the  double  bond  occurs,  with  the 
formation  of  camphene  glycol,2  CioHi6(OH)2;  but  if  for  the 
permanganate  we  substitute  nitric  acid,  the  first  product 
isolated  is  camphoic  acid.3  Just  as  malonic  acid  on  dry 
distillation  loses  carbon  dioxide  and  is  converted  into  acetic 
acid,  so  camphoic  acid  loses  carbon  dioxide  and  yields 
apocamphoric  acid.  From  this  we  may  deduce  that  cam- 
phoic acid  is  a  tribasic  acid  of  the  constitution  shown  below — 


1  Bredt,  Annalen,  1898,  299,  150. 

2  Wagner,  Ber.,  1890,  23,  2311. 


3  Marsh  and  Gardner,  Trans.,  Chem.  Soc.,  1891,  59,  61;  1896,  69,  74. 

G 


82      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 
CH2 CH COOH  CH2 CH COOH 


CH3— C— CH3 


CH3— C— CH 


3 

OH2-      -C-      -COOH  CH2-      -CH COOH 

COOH 

Camphoic  acid.  Apocamphoric  acid. 

The  constitution  of  apocamplioric  acid  is  established  by 
the  fact  that  it  can  be  prepared  by  the  reduction,  under 
suitable  conditions,  of  diketoapocamphoric  acid  with  which  we 
have  already  dealt. 

We  must  now  leave  the  camphor  group  and  turn  to  the 
isomeric  substances  in  the  fenchene  and  pinene  series. 

B. — FENCHONE  AND  ITS  DERIVATIVES. 
1.  The  Constitution  of  Fenchene. 

Fenchone  is  a  ketonic  compound,  isomeric  with  camphor, 
and  resembling  it  in  many  respects.  When  dextro-fenchone  is 
reduced  it  yields  D-Z-fenchyl  alcohol1;  the  name  indicates 
that  though  derived  from  a  dextro-ketone  the  substance  is 
actually  laevo-rotatory.  When  this  is  treated  at  a  low  temperature 
with  phosphorus  pentachloride  it  gives  laevo-rotatory  D-Z-fenchyl 
chloride;  which,  by  the  action  of  aniline,  loses  hydrochloric 
acid  and  is  converted  into  D-Z-fenchene,  just  as  bornyl  chloride 
is  changed  into  carnphene.  If  the  reaction  mixture  during 
the  formation  of  fenchyl  chloride  be  allowed  to  grow  warm, 
the  resulting  substances  are  not  D-Z-fenchyl  chloride  and 
D-Z-fenchene,  but  D-tZ-fenchyl  chloride  and  D-tZ-fenchene. 

The  constitution  of  D-Z-fenchene  has  been  dealt  with  in  the 
following  way.2  When  it  is  oxidized  with  potassium  permanga- 
nate it  is  converted  into  a  hydroxy-acid,  D-Z-hydroxy-fenchenic 
acid,  which  has  the  composition  Ci0Hi603.  This  body,  when 
treated  with  lead  peroxide  and  sulphuric  acid,  loses  carbon 
dioxide  and  two  atoms  of  hydrogen,  being  converted  into 
D-^-fenchocamphorone,  CgH^O.  By  nitric  acid  this  last  com- 
pound is  broken  down  to  apocamphoric  acid.  This  production 

1  Wallach,  Annalen,  1891,  263,  143. 

2  Wallach,  Annalen,  1898,  300,  294;  1901,  315,  283. 


THE   DICYCLIC   TERPENES 


of  apocamphoric  acid  from  fenchene  shows  that  in  fenchene 
itself  one  of  the  carbon  atoms  must  be  attached  to  the  nucleus 
at  a  point  different  from  that  at  which  the  methyl  group  in 
camphor  is  placed  as  otherwise  we  should  find  camphoric  acid 
produced  in  the  end  instead  of  its  next  lower  homologue,  apo- 
camphoric acid.  The  only  way  in  which  we  can  satisfy  this 
requirement  is  shown  in  the  formulae  below — 


CH2 CH C :  CH2     C] 


CH3— C— CH3 


CH C(OH).  COOH 


CH3-C— CI 
— CH- 


LS 


CH2 CH CH2         CH2 — 

D-Z-fenchene.  Hydroxyfenchenic  acid. 


CH2 


-CH CO 


CH, 


-CH .  COOH 


CH3— C— CH3      |   —  - 
CH- 


CH3— C— CH3 

I  I 

CH2 CH.COOH 

Apocamphoric  acid. 


Fenchocamphorone. 
D-Z-fenchene,  therefore,  has  the  constitution  expressed  by — 
CH2—      -CH—      -C :  CH2 

CH3 — C — CH3 
CH2 CH CH2 


2.  The  Constitution  of  Fenchone  and  Fenchyl  Alcohol. 

Claisen l  has  shown  that  when  ketones  containing  a  methyl- 
ene  group  next  the  carbonyl  radical  are  treated  with  sodium 
and  amyl  formate  they  are  converted  into  oxymethylene 
derivatives — 


E— CH2 
R— CO 


R_C  :  CH  .  OH 


E— CO 


Camphor  when  dealt  with  in  this  manner  forms  oxymethylene 
1  Claisen,  Annalen,  1894,  281,  394. 


84      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 


camphor  ;  but  when  we  apply  the  same  reaction  to  fenchone  no 
such  result  is  obtained.  From  this  we  conclude  that  fenchone 
contains  no  methylene  group  next  the  carbonyl  radical. 

We  have  just  proved  the  formula  of  D-Z-fenchene,  and  from 
it  we  can  deduce  that  of  the  corresponding  saturated  compound, 
fenchane  — 


}H C :  CH2     CH 


CH3— C-CH3 
-CH 


CH  .  CH3 


D-Z-fenchene. 


Now,  fenchone  is  derived  from  fenchane  by  replacing  a 
methylene  group  by  a  carbonyl  radical,  and,  in  accordance  with 
what  we  have  just  shown,  the  carbonyl  group  so  produced  must 
have  no  methylene  group  adjacent  to  it.  There  is  only  one 
formula  which  fulfils  these  conditions,  so  that  the  constitution 
of  fenchone  must  be  expressed  by — 


CH2 


CH 


CH  .  CH3 


CH3 — C-^CH3 

—in— 


CO 


Fenchone. 


Since  fenchyl  alcohol   is   obtained   by  the    reduction    of 
fenchone,  its  constitution  must  be  that  which  is  shown  below — 


CH2 CH CH.CHg   CH2 

CH3 — C — CH3 


CH2 CH — 

Fenchone. 


-CO 


-CH— 
-C~ 


CH.CH3 


CH, 


-CH CH  .  OH 


Fenchyl  alcohol. 


Another   formula    for   fenchone    has    been    suggested    by 
Semmler1  and  supported  by  Bouveault  and  Levallois2— 

1  Semmler,  Ch.  Zig.,  1905,  29,  1313. 

2  Bouveault  and  Levallois,  C.  r.,  1908,  146,  180. 


THE  DICYCLIC   TERPENES 


CH, 


OH, 


-CH- 

CH2 

-0— 


OH, 


•C(CH3)2 


-CO 


This  formula  explains  certain  reactions  which  Wallach's 
does  not  make  clear.     The  matter  is  still  under  discussion. 


C.— PINENE. 

1.  The  Constitution  of  Pinene. 

Pinene  is  a  hydrocarbon  isomeric  with  camphene  and 
fenchene.  It  was  found  by  Sobrero 1  that  when  this  substance 
was  allowed  to  stand  in  sunlight  in  contact  with  water  and 
air  it  was,  after  several  months,  converted  into  a  compound 
sobrerol,  CioHj6(OH)2,  which,  on  boiling  with  dilute  acids,  was 
changed,  by  the  loss  of  one  molecule  of  water,  into  pinol, 
CioHieO.  Pinol  was  found,  on  further  investigation,  to  be  an 
internal  ether  of  the  same  type  as  cineol.  Wallach 2  has  shown 
that  pinol  may  also  be  obtained  by  the  action  of  sodium  ethylate 
on  terpineol  dibromide. 

When  pinol  or  sobrerol  is  treated  with  a  one  per  cent,  solution 
of  potassium  permanganate  the  product  is  a  dihydric  alcohol,8 
pinol-glycol,  CioHi60(OH)2.  On  further  oxidation,  a  tetra- 
hydric  alcohol,4  sobrerythrite,  CioH^OH)*,  is  formed,  which  in 
turn  is  oxidized  to  terpenylic  acid.  Therefore  we  should  find 
in  pinene,  pinol,  and  pinol-glycol,  the  same  chain  of  carbon 
atoms  which  we  know  exists  in  terpenylic  acid— 


COOH 


1  Sobrero,  Annalen,  1851,  80,  106. 

2  Wallach,  Annalen,  1890,  259,  309. 

8  Wagner  and  Slawinski,  Ber,  1894,  27,  1644. 

4  Wagner  and  Ginsberg,  Per.,  1894,  27,  1648;  1896,  29,  1195. 


86      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

In   other  words,   the    pinol    skeleton   must    contain    the 
grouping— 

CH2 CH CH2 


CH3 — C — CH3 


CH  = 


=  C 


Into  this  scheme  we  have  now  to  fit  a  hydrogen  atom  and 
the  group — 

CH*— C  : 


and,  as  can  at  once  be  seen,  there  are  two  possible  ways  of 
doing  this — 


CH2 CH 

CH3— C-CH3 

X0 


CH2 


-C- 


CH3 

Pinol  T. 


CH CH, 

CH3— C— CH3 

X0 

\ 
CH2 C==    =0 

CH3 

Pinol  II. 


On  these  two  assumptions  sobrerol,  which  is  obtained  from 
pinol  by  the  addition  of  water,  would  have  either  of  the 
formulae — 


US.1% 

Cl 
"!TT 

?a  —  C  —  CH3 
OH 

o           r 

H.OH       ( 

CH3  —  C  —  CH3 

AH 

^H             C                ( 

LOH 

CH3 

Sobrerol  l.a. 

CH3 
Sobrerol  Il.a. 

Now,  sobrerol,  on  oxidation  with  a  one  per  cent,  solution  of 
potassium  permanganate,  gives  a  tetrahydric  alcohol,  sobrery- 


THE  DICYCLIC   TERPENES 


thrite.     This  can  only  be  explained  by  using  the  formula  (I.a), 
for  (Il.a)  would  produce  a  hydroxy-ketone — 


CHS 


-CH- 


-CH, 


—  C  —  CH3 

AH 


CH2 CH- 

I 


-CHc 


C 


3.  OH 


CH3 —  C — CH3 

AH 

CH2 CO         COOH 

CH3 

Hydroxyketone. 

Sobrerol,    therefore,    has    the    formula    (La)    and    pinol    the 
formula  (I.). 

From  this  we  may  conclude  that  the  formula  of  pinene 
itself  is — 

CH2 CH CHS 


H3 
Sobrerol  Il.a. 


CH2 

Pinene. 

In  virtue  of  the  double  bond  in  its  molecule,  pinene  is 
capable  of  uniting  with  hydrochloric  acid  or  nitrosyl  chloride. 
Pinene  hydrochloride  resembles  camphor  in  appearance  and 
smell,  and  is  used  commercially  under  the  name  of  "  artificial 
camphor."  Pinene  nitroso-chloride,1  on  standing  in  presence  of 
hydrochloric  acid,  is  converted  into  hydrochlorocarvoxime  by 
the  wandering  of  a  chlorine  atom  and  the  rupture  of  the  pinene 
tetramethylene  ring. 


OH 


0x1 


C  H3 — C — C  H3 

i. 


CH 


C- 


CH 


Pinene  nitrosochloride. 


N.OH      CH3 

Hydrochlorocarvoxirae. 


Baeyer,  Ber.t  1896,  29;  20. 


88      RECENT  ADVANCES  IN   ORGANIC   CHEMISTRY 


Pinene  itself  is  converted  into  terpineol  by  hydration  with 
dilute  acids — 

J OJtl Oll9 

CH3— C— ( 
OH 


^iA2     -                    V^/XJ.       - 

CH  3  —  0  —  v^H3 

;AJL2 

N. 

\ 

ITT          r             f 

3H 

CH3 

Pinene. 

CH; 


Terpineol. 

2.  Pinonic  and  Pinic  Acids 

When  pinene  is  oxidized  with  potassium  permanganate, 
the  first  product  is  a  ketonic  acid  l  which,  according  to  the 
conditions  of  the  experiment,  can  be  obtained  either  as  a  single 
substance  or  as  a  mixture  of  two  isomers.  When  the  single 
substance  is  produced  it  is  found  to  have  the  composition 
CioHi603,  and  has  been  named  a-pinonic  acid.  It  contains  the 
group  CH3 — CO — ,  for,  on  treatment  with  bromine  and  potash, 
it  loses  a  methyl  group,  takes  up  hydroxyl,  and  is  converted 
into  pinic  acid,  CgHuCV- 

KOH  and  Br 

C8Hi302— CO— CH3  -       >  C8Hi302— COOH  +  CHBr8 

Pinonic  acid.  Pinic  acid. 

These  changes  are  expressed  in  the  following  formulae : — 
CH2 CH CH2  CH2 CH CH2 


CH3— C— CH3 
==0 — CH 


CH3— C— CH3 
COOH        CO -CH 


CH3 

Pinene. 


CH8 

Pinonic  acid. 


CH2 CH CH2 

CH3 — C —  CH3 

COOH        HOOC CH 

Pinic  acid. 

1  Baeyer,  Ber.,  1896,  29,  3. 


THE  DICYCLIC   TERPENES 


89 


Now,  on  hydrolysis  with  fifty  per  cent,  sulphuric  acid, 
pinonic  acid  gives  a  keto-lactone,1  Ci0H1602,  which  proves  to  be 
identical  with  that  obtained  in  the  oxidation  of  terpineol.  A 
similar  hydrolysis  converts  pinene  into  terpineol,  so  that  we 
may  draw  up  the  following  scheme  to  show  the  relations 
between  the  four  substances  : — 
CH2 CH Cttj 

CH3— C- 
CH 

CH3 

^  hydrolysis 
CH2 CH CH2 

CH3-C-CH, 


Pinene. 


CH3  oxidation 


CH CH2 

CH3— C— CH3      I       Pinonic  acid. 
OH       CO CH 


Terpineol. 


oxidai 
OH  


oxidation 


CH 


Ketolactone. 


CH2 


D. — BORNYLENE  AND  THE  THUJENES 
In   this   section  we  may  deal  very  briefly  with   the  two 

substances,  bornylene  and  thujene. 

Bornylene  is  obtained  from  bornyl  iodide  by  the  action  of 

alcoholic  potash.     On  oxidation  it  gives  camphoric  acid.     From 

this  we  can  deduce  that  its   formula  must  be  that  which  is 

shown  below — 

CH2 CH CH2 

I 

OHq 0 OHq 


CH, 


CH.I 


CH3 

Bornyl  iodide. 

CH5 


-/-LJ-2     ~                 \JJ-1                          v 

CH3—  C—  CH3 
^TT           r              r 

/a  j. 
JH 

CH3 

Bornylene. 

CH COOH 


CH3— C— CH3 
CH9 C COOH 


CH3 

Camphoric  acid. 

1  Baeyer,  Ber.,  1896,  29,  3. 


90      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

Thujone  is  a  ketone  isomeric  with  camphor.  Its  consti- 
tution has  not  yet  been  established  by  a  synthesis,  but  at  the 
present  time  it  appears  almost  certain  that  it  has  the  formula 
ascribed  to  it  by  Semmler,1  in  which  it  is  represented  as  a 
combination  of  a  six-membered  with  a  three-membered  ring  — 

CH3   CH3 

¥  i 

C  IT2  —  C 


CH  —  CH—  CO 
I 
CH3 

When  thujone  is  reduced  it  yields  thujyl  alcohol  ;  and  from 
this  we  can  produce  the  thujyl  derivative  of  xanthogenic  acid 
(sulphothio-carbonic  acid).  When  this  substance  is  distilled  it 
breaks  down  into  carbon  oxysulphide,  methyl  mercaptan,  and  a 
hydrocarbon,  thujene  — 

C10H170  .  OS  .  SCH3  =  COS  +  CH3SH  -f  C10H16 

Tschugaeff  2  has  shown  that  thujene  thus  obtained  is  a  mixture 
of  two  hydrocarbons,  to  which  he  attributes  the  formulae— 

03117  03x17 

CH2—  C—  CH2  OH2-C  ---  CH 

I  I  \/\ 

CH  —  C=CH  CH—  CH  —  CH 


CH3  CH3 

a-Thujene.  £-Thujene. 

1  Semmler,  Ber.,  1900,  33,  275,  2459. 

2  Tschugaeff,  Ber.t  1901,  34,  2279;  1904,  37,  1481. 


CHAPTEE  V 

THE  OLEFINIC   TERPENES 

A. — INTRODUCTION 

WE  have  now  described  all  the  important  cyclic  terpenes,  and 
in  pursuance  of  the  plan  laid  down  in  the  first  section  dealing 
with  these  bodies,  we  must  next  examine  the  olefinic  substances 
which  are  often  included  in  the  terpene  group.  It  might  have 
been  more  logical  to  have  dealt  with  the  open-chain  compounds 
first,  and  the  cyclic  ones  later,  but  as  we  should  in  that  case 
have  had  to  assume  the  constitution  of  certain  cyclic  terpenes 
which  are  closely  connected  with  the  olefinic  ones,  the  present 
method  of  arrangement  is  more  convenient. 

Those  unsaturated  open-chain  substances  which  are  found  in 
ethereal  oils,  and  which,  in  many  cases,  can  be  transformed  into 
cyclic  terpenes,  are  termed  olefinic  terpenes,  or  terpenogens. 
They  occur  as  hydrocarbons,  aldehydes,  or  alcohols,  and  are 
derived  from  hydrocarbons  of  the  formula  C5H8.  In  many 
cases  the  odour  of  ethereal  oils  is  very  largely  due  to  the  olefinic 
terpenes  contained  in  them. 

The  chemical  importance  of  the  olefinic  terpenes  lies  in  the 
fact  that  from  them  we  can  build  up  some  of  the  more 
complicated  terpene  derivatives  by  means  of  very  simple 
reactions  ;  but  they  are  of  interest  also  from  the  commercial 
point  of  view  as  forming  the  basis  of  many  natural  and 
artificial  perfumes. 

B. — ISOPRENE. 

Isoprene  is  the  simplest  of  all  the  olefinic  terpenes;  it 
contains  two  double  bonds,  and  has  the  composition  C5H8.  Its 
synthesis  has  been  carried  out  by  Euler,1  and  also  by  Ipatjew,2 

1  Euler,  J.  pr.  Ch.,  II.  57,  132. 

2  Ipatjew,  ibid.,  55,  4. 


92      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

in  the  one  case  starting  from  methyl-pyrrolidine,  and  in  the 
other  from  dimethyl-allene.  In  the  first  case,  the  inethyl- 
pyrrolidine  (I.)  is  allowed  to  interact  with  methyl  iodide  with 
the  formation  of  dimethyl-methylpyrrolidinium  iodide  (II.). 
This  substance  is  then  decomposed  with  potash,  whereby  the 
ring  is  broken  and  fe-dimethyl-methylpyrrolidine  (III.)  is 
produced.  The  addition  of  methyl  iodide  and  decomposition  of 
the  product  (IV.)  with  potash  gives  trimethylamine  and  the 
required  isoprene  (V.). 

a.)  (no  cm.) 

CH3— CH— CH2         CH8— CH— CH2  CH3— OH— CH 

CH2   CH2  CH2    CH2  CH2   CH2 

\/  \ 

CH3— N— I  N(CH3)2 


CH, 


(IV.)                              (V.) 
CH3— CH— CH  CH0  -  C CH 

— 


.  CH2 

N(CH3)3 

+  N(CH3)3  +  HI 

The  synthesis  from  dimethyl-allene  is  much  simpler.  Two 
molecules  of  hydrobromic  acid  are  added  on,  forming  2-  methyl-2, 
4-dibromobutane,  from  which  hydrobromic  acid  is  again  split  off 
by  means  of  alcoholic  potash — 

CH3  CH3  CH3 

C  :  C  :  CH2  CBr .  CH2 .  CH2Br  C .  CH  :  CH2 

/  /  S 

riTT  r^TT  f^TT 

v^/jLi3  v-'-tis  v-^-da 

Dimethyl-allene.  Methyl-dibromobutane.  Isoprene. 

Isoprene  is  produced  by  the  dry  distillation  of  indiarubber 
and  by  the  decomposition  of  turpentine  oil  at  a  dull  red  heat. 
Concentrated  hydrochloric  acid  converts  it  into  a  polymer  which 
has  all  the  physical  properties  of  indiarubber,  and  the  same 
change  takes  place  on  long  standing  or  with  traces  of  acids  in 


THE   OLEFINIC   TERPENES  93 

sunlight.     When  heated  to  300°  C.,  isoprene  is  polymerized  to  a 
di-isoprene,  which  seems  to  be  identical  with  dipentene.1 


i  c 

/\  /\ 

H2C        OH  H2C        CH 

II  I          I 

H2C        OH2  H2C        CH2 

\  \/ 

CH  CH 


i 


C 

0x12 


In  a  somewhat  similar  manner  isoprene  might  be  supposed 
to  give  a  sesquiterpene  in  which  three  isoprene  molecules  would 
coalesce  to  form  a  compound  of  the  composition  Ci5H24.  In  any 
probable  reaction  of  this  type,  it  is  worth  noting,  at  least  one 
unsaturated  chain  will  be  left  untouched  and  ready  to  react 
with  further  molecules  if  the  proper  conditions  are  obtained  ; 
and  it  is  doubtless  to  this  side  chain  that  we  owe  the  more 
complex  polymer  which  resembles  indiarubber. 


C.— ClTKONELLAL. 

We  must  now  pass  to  the  consideration  of  a  substance  rather 
more  complicated  than  isoprene — the  compound  citronellal, 
which  was  discovered  by  Dodge 2  in  citronella  oil.  Citronellal 
is  an  aldehyde,  for  on  reduction  it  gives  the  alcohol  citronellol, 
and  on  oxidation  it  forms  citronellic  acid.  Since  it  is  optically 
active  it  must  contain  an  asymmetric  carbon  atom. 

Tiemann  and  Schmidt,3  oxidizing  it  in  aqueous  solution, 
obtained  as  products  acetone  and  |3-methyl-adipic  acid,  from 
which  they  concluded  very  naturally  that  citronellal  had  the 
constitution — 

1  Tilden,  Trans.  Chem.  Soc.,  1884,45,410 ;  Bouchardat,  C.  R.,  1875,  80, 1446 ; 
1878,  87,  654  ;  1879,  89,  361,  1117. 

2  Dodge,  Am.  Chem.  J.,  1889,  11,  456. 

8  Tiemann  and  Schmidt,  Per.,  1896,  29,  903 ;  1897,  30,  22,  33. 


94      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 
(CH3)2C  =  CH .  CH2 .  CH2 .  CH(CH3) .  CH2 .  CHO 


V 

(CH3)2CO  +  CH2 .  CH2 .  CH(CH3) .  CH2 .  COOH 
COOH 

The  reason  for  placing  the  methyl  group  in  this  position  will  be 
seen  later  when  we  deal  with  the  production  of  pulegone  from 
this  body. 

This  constitution,  however,  is  not  in  agreement  with  the 
work  of  Harries  and  Schauwecker,1  who  approached  the  matter 
from  a  slightly  different  standpoint.  Instead  of  oxidizing 
citronellal  itself,  they  prepared  its  dimethyl-acetal  and  replaced 
the  aqueous  solution  of  Schmidt  and  Tiemann  by  an  acetone 
one.  Under  these  circumstances  they  found  that  the  oxidation 
product  with  potassium  permanganate  was  the  acetal  of  a 
dihydroxy-dihydrocitronellal,  which,  on  further  oxidation  with 
chromic  acid,  could  be  converted  into  a  keto-aldehyde.  This 
shows  that  the  double  bond  must  lie  at  the  extreme  end  of  the 
chain,  so  that  citronellal  would  have  the  constitution — 

CH3  CH3 

C  .  CH2 .  CH2 .  CH2 .  CH .  CH2 .  CHO 

CH2 

On  this  view  the  dihydroxy-compound  and  the  keto-aldehyde 
would  be — 

CH3  CH3 

C(OH) .  CH2 .  CH2 .  CH2 .  CH .  CH2 .  CHO 

CH2OH 

CH3  CH3 

CO  .  CH2 .  CH2 .  CH2 .  CH .  CH2 .  CHO 

The  results  obtained  by  Tiemann  and  Schmidt  would  be 
explained  by  supposing  that  under  the  influence  of  the  aqueous 
oxidizing  agent  the  position  of  the  double  bond  was  changed 

1  Harries  and  Schauwecker,  Ber.,  1901,  34,  1498,  2981. 


THE   OLEFINIC   TERPENES  95 

from  the  ultimate  to  the  penultimate  pair  of  carbon   atoms 
in  the  chain. 

So  far  we  have  not  proved  the  position  of  the  methyl  group, 
but  we  shall  now  give  some  evidence  bearing  upon  the  point. 
When  citronellal  is  allowed  to  stand  by  itself  for  a  considerable 
time  it  is  converted  into  the  isomeric  substance  isopulegol.1 
The  same  change  is  brought  about  more  rapidly  by  heating 
citronellal  with  acetic  anhydride 2  to  180°  C.  The  change  may 
be  represented  in  the  following  manner  : — 

CH3  CH3 

CH  CH 

H2C          CH2  H2C          CH2 

II  II 

H2C          CHO  H2C          CH.OH 

CH2  CH 

I  I 

r\  r\ 

/\ 

CH3 

Citronellal.  Isopulegol. 

The  proof  of  the  constitution  of  isopulegol  depends  upon  its 
conversion  into  pulegone.  When  it  is  oxidized  it  yields  the 
ketone  isopulegone,  which  is  converted  into  pulegone  by  the 
wandering  of  a  double  bond. 

CH3  CH3  CH3 

CH  CH 

H2C          CH2  H2C         CH2  H2C        CH2 

H2C          CH.OH  H2C         CO  H2C        CO 

\  /  \  /  \  / 

CH  CH  C 

I  I  II 

C  C  C 

/  \  /  \  :  1  /  \ 

CH3        CH-2  CH3        OH  2  C-tL3        CJti3 

Isopulegol.  Isopulegone.  Pnlegone. 

1  Labbe,  Bull.soc.  chim.,  1899,  [ill]  21,  1023. 

2  Tiemann  and  Schmidt,  Ber.,  1896,  29,  913;  30,  27 


96      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

From  this  it  is  evident  that  the  methyl  group  in  citronellal 
must  be  in  the  position  which  we  attributed  to  it  as  otherwise 
the  isopropylene  group  would  not  come  into  the  1,  4-position 
with  it  in  the  pulegone  formed  from  citronellal. 

We  may  postpone  the  consideration  of  the  alcohol  citronellol 
and  of  citronellic  acid  until  later,  as  they  are  closely  connected 
with  some  members  of  the  class  of  compounds  with  which  we 
are  about  to  deal  in  the  next  section. 


D. — THE  CITEAL  GROUP. 
1.  General. 

The  group  of  olefmic  terpenes,  of  which  citral  is  the  most 
important  member,  can  all  be  derived  from  the  unsaturated 
ketone  methyl-heptenone.  It  will  perhaps  be  best,  before 
entering  upon  a  detailed  consideration  of  the  group  to  give 
a  small  table  showing  the  relations  between  the  different 
members. 

Methylheptenone 


acid 

X 

Citral  Rhodinic  acid 

/  \  /     \          I 

Geraniol  Nerol  Rhodinol  Rhodinal 

.  * 

Linalool 

We  must  now  proceed  to  trace  out  the  various  changes  by 
which  the  several  substances  are  obtained. 


2.  Methyl-heptenone. 

As  can  be  seen  from  the  foregoing  table,  the  substance  from 
which  all  the  other  members  of  the  citral  group  are  built  up  is 
the  ketone  methyl-heptenone.  We  have  already  encountered 
this  compound  among  the  decomposition  products  of  cineolic 
acid,  but  in  that  place  we  did  not  deal  with  its  constitution. 

Methyl-heptenone  has  been  synthesized  in  different  ways 


THE   OLEFINIC   TERPENES  97 

by  Barbier  and  Bouveault,1  Verley,2  Tiemann,3  Leser,4  and 
Ipatjew.5  We  need  only  give  one  synthesis  here,  and  may 
choose  that  of  Barbier  and  Bouveault.  In  the  first  place, 
2-methyl-2,  4-dibromobutane  is  condensed  with  the  sodium 
derivative  of  acetylacetone.  This  gives  the  unsaturated  dike- 
tone  (II.),  which  can  be  broken  down  by  strong  alkali  into 
acetic  acid  and  methyl-heptenone  (III.). 

(CH3)2C.Br  (CH3)2C  (CH3)2C 

CH2  CH  CH 

CH2Br  CH2  CH2 

CH3 .  CO  CH3 .  CO  CH3 .  CO .  CH2 
CH.Na                          CH 

CH3.CO  CH3.CO  CH3.CO.OH 

(I.)  (II.)  (HI.) 

This  establishes  the  constitution  of  the  substance,  but  if 
further  proof  were  required  it  is  to  be  found  in  the  behaviour  of 
methyl-heptenone  (A)  on  oxidation.  The  first  product  (B)  is  a 
dihydroxy-ketone,  which,  on  further  oxidation,  breaks  down 
into  acetone  and  laevulmic  acid  (C). 


CH 


C  C— OH 

CH3 
CH  >  CH .  OH 

CH2 .  CH2 .  CO .  CH3  CH2 .  CH2 .  CO 

(A.)  (B.) 

1  Barbier  and  Bouveanlt,  C.  #.,1896,  122,  393. 
8  Verley,  Bull  soc.  eta.,  1897,  [iii.]  17, 180. 

3  Tiemann,  Ber.,  1898,  31,  824. 

4  Leser,  Bull.  soc.  chim.,  1897,  [iii.]  17, 180. 

5  Ipatjew,  Ber.,  1901,  34,  594. 


98      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 
CH3 

— »  v:    .     ;:  • 

CHg 

COOH 

CH2.CH2.CO.CH3 

(C.) 

In  itself,  methyl-heptenone  is  of  no  great  importance,  and 
we  may  confine  ourselves  to  one  of  the  reactions  which  it 
undergoes.  When  shaken  with  seventy-five  per  cent,  sulphuric 
acid  it  loses  a  molecule  of  water  and  is  converted  into 
dihydro-m-xylene — 


,} 

HBC 


CH  CH 

/  \  S  \ 

CH3— C          CH2  CH3— C          CH2 

I          -H20  |               | 

CH2 >        HC  .       CH2 

0:C  XC 

CH3  CH3 

Methylheptenone.  Dihydro-w-xylene. 


3.  Geranic  Acid. 

Following  upon  their  synthesis  of  methyl-heptenone, 
Barbier  and  Bouveault  1  were  enabled  to  synthesize  geranic  acid 
by  means  of  a  simple  series  of  reactions  with  which  we  must 
now  deal.  By  the  action  of  zinc  and  iodo-acetic  ester  upon 
methyl-heptenone  they  prepared  a  hydroxy-acid,  which,  on 
boiling  with  acetic  anhydride,  broke  down  into  geranic  acid. 


31  825  '  R"  1896'  122>  393  •'  seealso  Tiemann,  Per.,  1898, 


THE   OLEFINIC   TERPENES  99 

The  formulae  below  indicate  the  course  of  the  synthesis — 


I          ?H' 

(CH3)2C  :  CH .  CH2 .  CH2 .  CO 

I    Zinc  and  iodoacetic  ester 

CH3 
(CH3)2C :  CH .  CH2 .  CH2 .  C .  OZnl 


Methyl-heptenone. 


Intermediate  product. 


CH2 .  COOEt 


Water 


CH3 

)H3)2C  :  CH  .  CH2  .  CH2  .  C  .  OH  Hydroxydihydrogeranic  ester. 

CH2.  COOEt 
Hydrolysis 


(CH3)2C  :  CH .  CH2  .  CH2  .  C  .  OH  Hydroxydihydrogeranic  acid. 

CH2COOH 

}    Dehydration  with  acetic  anhydride 

CH3 

(CH3)2C  :  CH .  CH2 .  CH2  .  C  :  CH  .  COOH       Geranic  acid. 

Like  methyl-heptenone,  geranic  acid  is  of  very  little 
importance  in  itself.  The  only  reaction  which  specially  con- 
cerns us  is  its  condensation  to  a-cyclogeranic  acid,1  which,  like 
the  corresponding  condensation  of  methyl-heptenone,  takes 
place  under  the  influence  of  seventy  per  cent,  sulphuric  acid. 
In  order  to  explain  the  geranic  acid  change,  it  is  necessary  to 
assume  the  formation  and  decomposition  of  an  intermediate 
product  which  has  not  yet  been  isolated — 

1  Tiemann  and  Semmler,  Ber.t  1893,  26,  2726 ;  Tiemann  and  Schmidt,  ibid., 
1898,  31,  881;  Tiemann  and  Tigges,  ibid.,  1900,  .33,  3713;  Barbier  and 
Bouveault,  Bull.  soc.  chim.,  1896,  [iii.]  15,  1002, 


TOO    RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 


CH3    CH 


HC 

I        II 
H2C        0  . 

CH2 


CH3    CH3 
VoH 
oC       CH2COOH 


CH 


o-Cyclogeranic  acid. 


CH3    CH3 

\x 

c 

CH .  COOH  H2C        CH .  COOH 

II                ^                   CH3  — ->     |          | 

/  H2C         C .  CH3 

H2C       C  \  // 

\/\ 
CH2     OH 

Geranic  acid.  Hypothetical 

intermediate  product 

As  the  table  shows,  geranic  acid  gives  rise  to  two  series  of 
compounds ;  on  the  one  hand,  by  reduction,  we  may  obtain 
rhodinic  acid  and  its  derivatives,  while  on  the  other  we  may 
produce  the  aldehyde  citral,  from  which  in  turn  several  sub- 
stances may  be  formed.  In  the  first  place,  we  may  deal  with 
the  smaller  group,  rhodinic  acid  and  its  allied  compounds. 

4.  Rhodinic  Acid,  Rhodinol,  and  RhodinaL 
When  the  ethyl  ester  of  geranic  acid  is  reduced  by  means 
of  sodium  and  amyl  alcohol  it  is  converted  into  inactive  rhodinic 
acid.1  The  active,  laevo-rotatory  form  of  this  acid  has  been 
obtained  from  the  active  alcohol  rhodinol.  These  two  acids 
are  isomeric  with  citronellic  acid,  which  is  obtained  by  the 
oxidation  of  the  aldehyde  citronellal,  and  it  has  been  suggested 
that  citronellic  acid  is  the  dextro-form  of  rhodinic  acid.  On 
the  other  hand,  from  the  constitution  of  citronellal,  we  should 
expect  that  citronellic  acid  obtained  from  it  by  oxidation  would 
have  the  formula  (I.),  while  rhodinic  acid  from  geranic  acid 
should  have  the  formula  (II.). 

CH2 :  C .  CH2 .  CH2 .  CH2 .  CH .  CH2 .  COOH 

CH8  CH3 

Citronellic  acid. 

(I.) 

(CH8)aO  :  CH .  CH2 .  CH2 .  CH .  CH2 .  COOH 

CH3 

Rhodinic  acid. 

(ii.) 

1  Tiemann,  Ber.,  1898,  81,  2901. 


THE   OLEFINIC    TERPENES  101 

The  literature  of  the  subject  is  somewhat  contradictory,  and 

it  does  not  seem  necessary  to  go  into  the  question  in  detail  here. 

When  the  ester  of  rhodinic  acid  is  reduced  by  means  of 

sodium  and  absolute  alcohol  it  yields  the  corresponding  alcohol 1 

rhodinol — 

(CH3)2C  :  CH .  CH2 .  CH2 .  CH .  CH2 .  CH2OH 

CH3 

which  is  isomeric  with  citronellol.  Here,  again,  the  literature 
is  contradictory,  and  it  seems  impossible  to  decide  whether  the 
two  compounds  are  stereo-isomers  or  differ  in  structure. 

Khodinal,2  the  aldehyde  corresponding  to  the  alcohol 
rhodinol,  is  obtained  by  distilling  together  calcium  formate  and 
the  calcium  salt  of  rhodinic  acid.  Barbier  and  Bouveault  regard 
it  as  having  the  structure  (I.),  because  of  its  conversion  into 
menthone.  Citronellal,  with  which  it  is  isomeric,  when  sub- 
mitted to  the  action  of  acetic  anhydride,  is  changed  into 
isopulegol,  as  we  have  already  described.  On  the  other  hand, 
rhodinal  when  treated  in  the  same  way  yields  menthone — 

CH3  CH3 

OH  OH 

\ 


H2C          CHO  H2C          CO 

\  \     / 

CH  CH 

II  I 

C  CH 

CH3    CH3  CH3        CH 

Khodinal.  Menthone. 

(i.)  (ii.) 

1  Bouveault  and  Gourmand,  C.  R.,  1901,  138,  1699. 

2  Tiemann,  Per.,  1898,  31,  2902. 


102    RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

5.  Citral. 

By  distilling  together  the  calcium  salts  of  formic  and 
geranic  acids  we  obtain  the  aldehyde  citral.1  Since  this  is  a 
general  reaction,  the  constitution  of  citral  svould  probably  be 
that  shown  in  the  equation  below — 

CH, 

(CH3)2C:CH.CH2.CH2.C:CH.COO-ca 
H.COO— ca 


I  CH, 

2.C:CH.COO-ca 

=  (CH3)20 :  CH.CH2.CH2.0 :  CH.CHO + CaC03 


In  support  of  this  formula  we  may  quote  the  decomposition 
of  citral  into  acetaldehyde  and  methyl-heptenone,  which  takes 
place  when  the  substance  is  warmed  with  a  solution  of  sodium 
carbonate. 

Citral,  therefore,  represents  rhodinal  or  citronellal,  from 
which  two  hydrogen  atoms  have  been  withdrawn ;  and  differs 
from  them  further  in  that  it  contains  no  asymmetric  carbon 
atom.  But  though  it  loses  this  possibility  of  isomerism,  it 
retains  another,  for  it  has  been  found  to  occur  in  two 
geometrically  isomeric  forms 2 — 

H— C— CHO 

II 

(CH3)2C :  CH .  CH2 .  CH2— C— CH3 
Citral  a. 

CHO— C— H 

II 
(CH3)2C :  CH .  CH2 .  CH2— C— CH3 

Citral  b. 

These  have  been  shown  by  Harries  and  Himmelmann  to 
be  structurally  identical ;  and  the  relative  configurations  have 
been  deduced  from  the  relations  of  the  two  compounds  to 
geraniol  and  nerol,  with  which  we  shall  deal  later. 

Like  the  other  olefinic  terpenes,  citral  can  be  converted  into 
cyclic  substances  with  great  ease.  When  it  is  boiled  for  a  long 
time  with  glacial  acetic  acid  it  is  changed  into  cymene  3 — 

1  Tiemann,  Ber.,  1898,  31,  827,  2899. 

2  Tiemann,  Ber.,  1899,  32,  115;  1900,  33,  877;  Bonveault,  Ball.  soc.  chim., 
1899,  [iii.]  21,  419,  423;  Barbier,  ibid.,  635;  Kerschbaum,  Ber.,  1900,  33,  886; 
Zeitschel,  Ber.,  1906,  39,  1783;  Harries  and  Himmelmann,  Ber.,  1907,  40,  2823. 

1  Tiemann  and  Semmler,  Ber.,  1895,  28,  2134. 


THE   OLEFINIC   TERPENES 
CH3  CH3 

v/ 

c 


103 


CH3   CH3 

\x 

c 


H 


H2C       CHOH 


H2C        CH2 

\/ 
C— OH 

CH, 


CH3 

Cymene. 

A  second  condensation  of  citral  takes  place  when  the 
aldehyde  group  is  so  treated  that  it  takes  no  part  in  the 
action.  For  instance,  if  we  condense  citral  with  a  primary 
amine,  we  obtain  a  cyclo-citral  by  a  simple  wandering  of  bonds 
and  ring-formation — 

CH3  CH3 


\ 

HC 

i 

\/                          ( 

c                             / 

'/                                         H2C 
CH.CH:N.R 

II                                                      -^ 

3-OH 
CH2.CH:Isr.E 

PTT                              -s 

il                         —r 
H,C       C  .  CH3         +  2H2o 

\  /                                  H2C 
CH2 

Citral  derivative.                                    C 

(i.) 

v^Jtl3                             s 

/                        -  2H20 

C 

H2      OH 
(II.) 

104    RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

CH,     CH,  CH8     CH3 

,/ 

C 

H2C        CH.CHrN.R          H2C        CH.CHO 


CH.CHrN.R          H2C        CH. 


H2C        C .  CH3  H2C        C .  CH3 

\  ^  \J* 

CH  CH 

a-Cyclocitral. 
(III.)  (IV.) 

The  same  result  may  be  obtained  by  condensing  citral  with 
cyan-acetic  ester  instead  of  an  amine.  In  each  case,  the  amine 
or  cyan-ester  can  be  split  off  after  the  condensation  to  cyclo- 
citral  has  taken  place. 

Cyclo-citral  occurs  in  two  isomeric  forms,1  the  formation  of 
either  being  dependent  upon  the  manner  in  which  water  is 
eliminated  from  the  molecule  of  an  intermediate  hydratioii 
product  (!!.)•  The  formation  of  /3-cyclocitral  takes  place  as 
shown  below. 


CH3     CH3 

\/ 

CH3     CH3 

CH3     CH3 

C—  OH 

\/ 

\/ 

/ 

C 

C 

H2C       CH2CH:N.R 

/\ 

/  \ 

H2C        O.CHiKR 

H2C        C.CHO 

CH3  3 

>       1         1]            > 

1          II 

/ 

H2C        C.CH3 

H2C        C.CH3 

H2C        C 

\/\ 

\   / 

CH2 

CH2 

CH2     OH 

j8-Cyclocitral. 

(II.) 

The  practical  interest  of  citral  lies  in  the  fact  that  when  it 
is  condensed  with  acetone  by  means  of  baryta,  it  yields  a 
substance,  pseudo-ionone,  which,  by  the  action  of  sulphuric 
acid,  is  changed  into  ionone,2  the  basis  of  artificial  violet 
perfume — 

1  Tiemann,  Ber.,  1900,  33,  3719. 

2  Tiemann  and  Kruger,  Ber.,  1893,  26,  2691 ;  Tiemann,  ibid.,  1898,  31,  808, 
867,  1736,  2313  ;  1899,  32,  827  ;  Tiemann  and  Schmidt,  {bid.,  1900,  33,  3703. 


THE   OLEFINIC   TERPENES 


105 


ft 
o 

o 

Q 

ft 
Q 


ft 


§-§  I 


W 
o 


t__  J 

ft 


o 

Q 

W 

ft 


g 

N**>' 


2- 

t 

g 


0    3 


o 

......... 

!W 


ft 

Q 


LQ.. 

Q 

ft 


w 


W 
o 

ft 
o 

6 


§ 


^ft 


W 
o 


io6    RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

This  body  differs  from  the  natural  substance  irone  (to  which 
the  odour  of  violets  is  due)  only  in  the  position  of  a  double 
bond-  CH 


C 

HC        CH .  CH  :  CH .  CO .  CH3 
HC        CH .  CH3 

CH2 

Irone. 

6.  Geraniol,  Nerol,  and  Linalool. 

If  we  reduce  citral  with  sodium  amalgam  in  an  alcoholic 
solution  weakly  acidified  with  acetic  acid,  a  mixture  of  two 
isomeric  alcohols,  geraniol  and  nerol,  is  obtained.  These  two 
bodies,  on  oxidation,  regenerate  citral,  and  on  this  ground,  as 
well  as  on  account  of  other  reactions  common  to  both,  it  is 
assumed  that  they  are  structurally  identical  but  stereoisomeric 
substances  of  the  formula —  CH3 

(CH3)2C :  CH .  CH2 .  CH2 .  C  :  CH .  CH2OH 

Proof  of  the  correctness  of  this  formula  is  afforded  by  the  fact 
that  when  geraniol  is  heated  with  water  to  150°  C.  it  gives 
ethyl  alcohol  and  methylheptenone ;  while  on  oxidation  it  gives 
acetone,  laevulinic  acid,  and  oxalic  acid. 

By  the  action  of  acetic  acid,  to  which  one  or  two  per  cent, 
of  sulphuric  acid  has  been  added,  both  nerol  and  geraniol  give 
terpineol — 

CH3  CH3  CH3 

I  I  I 
C                                    C                                    C 

/  \  /  \  /  \. 

H2C         CH  H2C         CH  H2C        CH 

H2C         CH2OH  H2C         CH2OH  H2C         CH2 

CH  CH2  CH 

II  I  I 

C  C— OH  C— OH 

CH3        CH3  CH3       CH3  CH3       CH3 

Geraniol.  Hypothetical  glycol.  Terpineol. 


THE   OLEFINIC   TERPENES  107 

Now,  this  reaction  takes  place  nine  times  faster  with  nerol 
than  with  geraniol ;  and  if  the  two  bodies  are  geometrical  isomers, 
this  difference  allows  us  to  draw  a  conclusion  with  regard  to  their 
configurations.1  A  comparison  of  the  two  formulas  below  will 
suffice  to  show  that  in  (I.)  the  groups  which  unite  to  form  the 
terpineol  ring  are  further  apart  in  space  than  they  are  in  (II.). 
The  ring-formation  will  therefore  occur  more  easily  in  the  case 
of  (II.)  than  in  that  of  (I.).  Hence  we  must  ascribe  to  geraniol 
the  first  formula,  and  to  nerol  the  second — 

H— C— CH2OH 

II 
(0x13)20  '.  OH  .  OH2 .  OH2 — 0 — CH3 

Geraniol. 

(I-) 
CH2OH— C— H 

(CH3)2C :  CH  .  CH2 .  CH2— C— CH3 
Nerol. 
(II.) 

We  are  now  able  to  deal  with  the  space  formulae  of  the  two 
citrals.  The  oxidation  of  geraniol  gives  a  mixture  of  citral  a  and 
citral  &,  in  which  citral  a  predominates ;  while  with  nerol  the 
proportions  are  reversed,  more  citral  b  being  formed.  From  this 
we  may  deduce  that  citral  a  has  the  same  configuration  as 
geraniol,  while  citral  b  has  its  groups  arranged  as  in  nerol — 

H— C— CHO 

II 

(CH3)2C :  CH .  CH2 .  CH2— C— CH3 
Citral  a  (Geranial). 

CHO— C— H 

(CH8)2C :  CH  .  CH2 .  CH2— C— CH3 

Citral  6  (Neral). 

Both  geraniol  and  nerol  are  found  in  nature  as  inactive 
substances,  which  agrees  with  the  formulas  which  we  have 
ascribed  to  them  above.  The  isomeric  compound,  linalool, 
however,  occurs  in  both  dextro-  and  Isevo-rotatory  forms,  and 
must  therefore  contain  an  asymmetric  carbon  atom.  The 
inactive  form  of  linalool  is  convertible  into  both  geraniol  and 
nerol  by  the  action  of  acetic  anhydride.  This  reaction  can  be 
explained  by  assuming  that  linalool  has  the  formula — 

1  Zeitschel,  Ber.,  1906,  39,  1780. 


io8    RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

OH 

(01X3)20 :  OH .  CH2 « CH2 .  0 .  CH :  CH2 

I 
OH3 

A  comparison  of  the  formulae  of  geraniol,  nerol,  and  this 
one  proposed  for  linalool  will  show  that  by  the  addition  of 
water  to  each  of  these  substances  we  can  produce  in  all  three 
cases  the  same  glycol  of  the  formula— 

CH3 

(CH3)2C :  CH .  CH2 .  CH2 . 0 .  CH2 .  CH2OH 


This  formation  of  a  common  hydration  product  suffices  to 
explain  the  interconvertibility  of  the  three  isomers ;  but  there 
is  one  point  which  seems  to  render  the  linalool  formula  rather 
doubtful.  When  we  take  laevo-linalool  and  treat  it  with  acetic 
anhydride,  terpineol  is  formed  along  with  nerol  and  geraniol ; 
and  this  terpineol  is  found  to  be  dextro-rotatory.  But  when 
we  compare  the  formulae  of  terpineol  and  linalool,  we  find  that 
the  asymmetric  carbon  atom  of  linalool  does  not  correspond  to 
that  in  terpineol;  in  fact,  the  atom  which  in  linalool  was 
asymmetric  is  now  not  asymmetric,  while  a  new  asymmetric 
carbon  atom  has  come  into  being.  How  optical  activity  can 
persist  through  such  a  change  as  this  appears  difficult  to  under- 
stand, unless  we  assume  that  it  is  a  case  of  asymmetric  synthesis 
similar  to  those  described  later  in  this  volume. 

CH3    CH3  CH,    CH3  CH3    CH2 

C— OH  C— OH  C— OH 

CH  CH 

/*\  /*\  _ 


CH2 


H3C 


H2C          CH2  H2C         CH 

X  v 

CH3       OH  CH3 

Intermediate  products.  d-Terpineol. 


This  terminates  our  survey  of  the  terpene  class.  In  con- 
clusion, we  may  append  to  this  chapter  a  table  showing  some  of 
the  possible  conversions  of  mono-cyclic,  di-cyclic,  and  olefinic  ter- 
penes  into  each  other,  and  also  into  members  of  the  benzene  series. 


THE   OLEFINIC  TERPENES 


109 


5  Hydrochloric 
r"    and  aniline     c 


CHAPTEE   VI 

THE  ALKALOIDS 

A. — GENERAL 

WHEN  we  attempt  to  define  what  we  mean  by  the  term 
"  alkaloid "  our  difficulties  are  not  small.  On  the  one  hand, 
our  definition  may  be  so  drawn  as  to  include  almost  every 
naturally  occurring  nitrogen  compound,  which  is  obviously 
useless  as  a  mode  of  classification ;  or  it  may  be  so  narrow  as  to 
exclude  some  of  the  most  important  of  the  substances  which  are 
usually  included  in  the  alkaloid  group.  The  most  general 
definition  is  perhaps  the  best ;  and  for  our  present  purpose  we 
shall  treat  as  alkaloids  those  naturally  occurring  substances 
which  contain  cyclic  chains,  of  which  at  least  one  member  is  a 
nitrogen  atom.  This  definition  opens  to  us  a  much  wider  field 
than  we  can  possibly  attempt  to  cover  in  the  space  at  our 
disposal,  and  in  the  following  pages  we  shall  aim  at  describing 
the  syntheses  and  constitutions  of  a  few  typical  compounds 
rather  than  at  a  survey  of  the  whole  subject. 

Practically  all  the  important  alkaloids  are  found  in  the 
tissues  of  vegetables  ;  and  if  we  except  xan thine  derivatives,  we 
might  have  modified  the  definition  given  above  by  limiting  the 
\  term  "  alkaloid  "  to  basic  substances  found  in  plants.  ) 

The  known  members  of  the  alkaloid  class  are  very  numerous, 
and  the  number  of  workers  in  the  field  has  been  great ;  this  was 
to  be  expected  from  the  pharmacological  importance  of  these 
substances,  which  renders  a  knowledge  of  their  structure  of  the 
utmost  value. 

As  the  following  pages  will  show,  the  chemistry  of  the 
alkaloids  resembles  that  of  the  aromatic  compounds,  in  that 
both  classes  seem  to  be  built  up  upon  the  basis  of  one 
substance.  In  the  aromatic  series  benzene  lies  at  the  root  of  all 
the  compounds  however  complicated  they  be;  while  in  the 


THE  ALKALOIDS  .          in 

alkaloids  pyridine  appears  to  be  equally  essential  And  just  as 
among  the  aromatic  types  we  find  a  benzene  ring  condensed 
with  other  cyclic  chains,  so  in  the  alkaloids  we  may  discover 
compounds  in  which  the  pyridine  ring  is  overlaid  with  others. 
Even  the  derivatives  of  the  purine  group  may  be  considered  to 
be  derived  from  pyridine  by  the  substitution  of  a  second  nitrogen 
atom  in  the  ring. 

According  to  Guareschi,1  the  alkaloids  are  the  degradation 
products  of  protoplasmic  action  in  plants.  They  do  not  seem 
to  be  again  assimilated  by  the  plant  once  they  are  formed,  but 
remain  in  the  saps  in  the  same  way  as  uric  acid  may  remain  in 
the  human  tissues.  Pictet 2  has  dealt  with  the  subject  in  some 
detail,  and  we  may  here  summarize  his  views. 

In  the  first  place,  he  believes  that  alkaloids  are  not  produced 
in  plants  by  direct  syntheses,  but  are  rather  to  be  regarded  as 
the  decomposition  products  of  much  more  complicated  sub- 
stances. But  as  soon  as  the  alkaloid  is  formed  in  the  plant,  it 
immediately  reacts  with  some  other  plant  product  to  form  a 
derivative.  For  example,  some  alkaloids,  such  as  soline,  are 
glucosides  as  well  as  alkaloids ;  so  that  it  is  probable  that  in  their 
case  the  first-formed  alkaloid  reacts  with  glucose  within  the 
plant-tissues.  A  more  common  case,  however,  is  that  in  which 
the  alkaloid  condenses  with  an  organic  acid,  as  in  the  case  of 
cocaine  or  atropine.  But  by  far  the  most  common  case  of  all  is 
that  in  which  the  alkaloid  reacts  with  an  alcoholic  radical, 
usually  methyl  alcohol,  to  form  an  ether.  In  this  class  of 
derivatives  the  action  of  formaldehyde  apparently  lies  at  the 
root  of  the  syntheses.  Alkaloids  which  contain  a  pyrrol  ring 
are  probably  derived  from  proteins  ;  and  it  is  noteworthy  that 
while  on  the  one  hand  Fischer  has  shown  that  albumen  on 
hydrolysis  gives  pyrrol  derivatives,  it  has  been  proved  by 
Nencki,  Koster,  Zaleski,  and  Marchlewski  that  the  same 
nucleus  is  to  be  found  in  haemoglobin  and  chlorophyll. 

With  regard  to  the  occurrence  of  the  alkaloids  in  nature, 
very  little  generalization  is  possible.  The  monocotyledons 
seem  to  be  the  richest  in  members  whose  tissues  produce  these 
substances ;  while  among  the  cryptogamia  there  appears  to  be 

1  Guareschi,  "  Alkaloide,"  p.  414. 

2  Pictet,  Arch.  soc.  phys.  nat.  Geneve,  1905,  IV.,  19,  329;  Arch.  d.  Pharm., 
1906,  244,  389, 


ii2    RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

no  alkaloid  formation.  Just  as  little  regularity  is  found  with 
regard  to  the  distribution  of  the  alkaloids  in  the  various 
portions  of  the  plants  themselves.  Though  no  general  rule  can 
be  formulated,  it  seems  probable  that  alkaloids  are  most  often 
found  in  the  fruits  and  sap,  or,  in  trees,  in  the  bark. 

Since  in  most  cases  alkaloids  occur  as  salts,  they  are 
obtained  from  the  actual  plant  tissues  by  the  action  of  alkali, 
which  liberates  the  basic  part  of  the  molecule.  If  this  be 
volatile  in  steam,  the  alkaloid  is  obtained  in  this  way ;  but  if  it 
be  not  thus  volatile  it  is  extracted  from  the  tissues  by  treating 
them  with  acids,  which  dissolve  the  alkaloids,  forming  solutions 
of  their  salts,  from  which  the  free  alkaloid  is  obtained  by  the 
action  of  alkali.  Final  purification  is  carried  out  by  crystalli- 
zation of  the  alkaloid  or  of  its  salts.  When  extraction  is 
carried  out  on  a  small  scale,  chloroform  is  often  used  to  remove 
alkaloids  from  the  tissues  in  which  they  occur. 

The  majority  of  alkaloids  are  solid  substances,  but  one  or 
two  are  liquids  which  can  be  distilled  without  decomposition. 
Nearly  all  of  them  have  powerful  actions  upon  the  animal 
organism ;  but  owing  to  our  ignorance  of  the  relation  between 
chemical  constitution  and  physiological  action,  not  much  can 
be  said  on  the  subject.  In  most  cases  alkaloids  are  found  to 
possess  laevo-rotation,  and  it  is  very  seldom  that  both  optically 
active  forms  are  found  in  nature. 

The  alkaloids  are  usually  classed  according  to  the  hetero- 
cyclic  rings  from  which  they  are  built  up.  Thus  •  we  have 
the  pyridine  alkaloids,  the  quinoline  alkaloids,  and  so  forth. 
For  our  present  purposes  this  system  of  classification  is  very 
suitable,  and  we  shall  therefore  deal  with  the  subject  under 
the  following  heads  : — 

The  Pyridine  Group. 
The  Pyrrolidine  Group. 
The  Quinoline  Group. 
The  Isoquinoline  Group. 
The  Purine  Group.        f 

There  is  another  series  of  substances,  the  morpholine  or 
phenanthrene  group,  but  the  constitutions  of  its  members  are  at 
present  undetermined,  so  we  shall  omit  it  from  our  survey. 


THE  ALKALOIDS  113 

B. — METHODS  EMPLOYED  IN  THE  DETERMINATION  OF 
ALKALOID  CONSTITUTIONS 

After  we  have  carried  out  an  elementary  analysis  of  an 
alkaloid  we  are  in  a  position  to  state  its  percentage  composi- 
tion, and  by  a  molecular  weight  determination  we  can  estimate 
the  number  of  atoms  which  its  molecule  contains.  The  next 
step  is  the  determination  of  the  mode  in  which  these  atoms 
are  linked  together  in  the  alkaloid  molecule,  and  we  shall  now 
give  a  brief  account  of  some  common  reactions  which  are 
employed  to  solve  this  problem. 

In  the  first  place,  since  many  alkaloids  are  known  to  be 
esters,  it  is  usual  to  employ  some  hydrolytic  method  in  order  to 
see  whether  or  not  the  alkaloid  molecule  can  be  decomposed 
into  some  simpler  grouping.  To  this  end,  the  alkaloid  may  be 
heated  with  water,  acids,  or  alkalis  until  it  is  decomposed  into 
its  component  acid  and  base.  This  method,  while  breaking 
up  any  salt  or  ester,  does  not,  except  in  a  few  cases,  result  in 
any  further  destruction  of  the  structure  of  the  body ;  so  that 
from  the  constitutions  of  the  two  halves  we  are  able  to  deduce 
the  constitution  of  the  parent  substance. 

This  method  of  decomposition,  however,  may  not  carry  us 
far  enough,  and  it  is  usually  seconded  by  a  more  violent  action. 
For  instance,  the  alkaloid  may  be  fused  with  alkali,  distilled 
with  zinc  dust,  heated  with  bromine  or  phosphoric  acid.  When 
reagents  such  as  these  are  employed,  the  less  durable  part  of 
the  molecule  is  usually  shattered ;  and  in  the  reaction-product 
we  find  some  stable  nucleus  such  as  pyridine,  quinoline,  or 
isoquinoline,  from  which  the  whole  alkaloid  is  derived. 

Again,  many  alkaloids  exist  in  the  form  of  methyl  ethers. 
These  can  be  broken  up  by  boiling  with  hydriodic  acid  (Zeisel's 
method);  and  by  passing  the  methyl  iodide  thus  formed  into 
silver  nitrate  solution  the  number  of  methyl  radicals  split  off 
by  the  hydriodic  acid  may  be  estimated,  and  thus  the  number 
of  methoxyl  groups  in  the  alkaloid  can  be  ascertained. 

When  the  alkaloid  contains  an  oxygen  atom,  it  is  of 
importance  to  determine  whether  this  occurs  in  a  carbonyl, 
carboxyl,  hydroxyl,  or  ether  group.  The  first  is  determined  in 
the  usual  way  by  the  action  of  phenylhydrazine  or  hydroxyl- 
amine;  the  hydroxyl  group  can  usually  be  detected  by 

I 


ii4      RECENT  ADVANCES  IN   ORGANIC   CHEMISTRY 

acylating  it  or  by  the  action  of  dehydrating  agents,  which 
split  off  water  and  leave  an  unsaturated  substance;  while  if 
the  alkaloid  is  an  alkyl  ether  it  can  often  be  decomposed  by 
Zeisel's  method.  If  the  carboxyl  group  occurs  in  the  alkaloid 
under  examination,  there  is  not  much  difficulty  in  detecting 
its  presence. 

All  alkaloids  contain  nitrogen,  but  it  is  necessary  to  dis- 
cover in  what  way  this  nitrogen  is  linked  with  the  rest  of 
the  molecule.  Herzig  and  Meyer  have  devised  a  method  of 
determination  for  methyl-imino  groups  which  is  very  useful  in 
this  branch  of  research.  The  hydriodides  of  bases  in  which  a 
methyl  group  is  attached  to  nitrogen,  when  heated  to  about 
300°  C.,  split  off  methyl  iodide,  which  can  be  estimated  with 
silver  nitrate  just  as  in  the  case  of  the  methoxyl  group.  A 
somewhat  similar  decomposition  results  in  the  reaction  which 
is  usually  termed  "exhaustive  methylation."  Here,  by  the 
action  of  methyl  iodide  and  silver  oxide,  assisted  by  dry  dis- 
tillation, a  cyclic  nitrogen  compound  may  be  made  to  lose  its 
nitrogen  atom  with  but  little  alteration  in  the  rest  of  the 
molecule.  The  formulae  will  make  the  process  clear  without 
further  explanation. 


CH, 
H2C'    NCH2    CH3I    H2C"  XCH,     Distill    H.CTH 


H,CX  ^CH,  AgaO     H,CX  sCH,  -H,O     H,C      CH, 

N 


H2C      XCH        Distill 

CHXCH 

H3C       CH, 
10-^N—  CH, 

CH;    XCH3 

CH2CH2 

N(CH3)3+  H20 


The  final  stages  in  the  constitution  determination  of  any 
alkaloid  are  usually  those  in  which  the  oxidation  products  of 
the  substance  are  studied.  We  need  not  describe  the  actions 


THE  ALKALOIDS  115 

of  the  various  agents  employed,  as  they  are  all  well  known. 
The  most  useful  are  potassium  permanganate,  hydrogen 
peroxide,  dilute  nitric  acid,  and  chromic  acid. 

We  must  now  proceed  to  the  examination  of  the  evidence 
which  has  been  collected  with  regard  to  the  syntheses  and 
constitutions  of  some  alkaloids. 

C. — THE  PYEIDINE  GROUP 
1.  Coniine. 

The  first  alkaloid  with  which  we  shall  deal  is  the  substance 
coniine,  which  deserves  the  foremost  place  on  two  grounds :  it 
is  the  simplest  member  of  the  alkaloid  class,  and  it  is  the 
first  alkaloid  which  has  been  completely  synthesized  from  the 
elements.  The  complete  synthesis  will  be  given  in  the  case  of 
this  substance,  as  it  is  of  historical  interest,  but  in  the  case  of 
the  other  synthetic  compounds  we  must  confine  ourselves  to 
the  later  steps  in  the  process. 

By  heating  together  carbon  and  sulphur  we  can  produce 
carbon  disulphide,  which,  by  the  action  of  chlorine,  is  converted 
into  carbon  tetrachloride.  By  heat,  this  can  be  changed  into 
perchlorethylene,  C12.C  :  C.C12,  and  when  this  is  acted  on  by 
ozonized  air  it  yields  trichloracetic  acid.  Eeduction  with 
potassium  amalgam  in  aqueous  solution  changes  trichloracetic 
acid  into  acetic  acid.  From  this,  acetone  is  obtained  by 
distillation  of  calcium  acetate,  and  by  reducing  the  acetone  so 
formed  we  can  produce  isopropyl  alcohol.  The  action  of  zinc 
chloride  upon  the  alcohol  gives  propylene  by  dehydration,  and 
by  the  addition  of  chlorine  we  can  then  form  propylene  chloride 
Propylene  chloride  and  iodine  chloride  together  yield  tri- 
f  chlorohydrin,  from  which  glycerine  is  obtained  by  heating  the 
trichloride  to  160°  with  a  large  excess  of  water.  Glycerine, 
by  dehydration,  gives  allyl  alcohol;  and  this,  in  turn,  allyl 
bromide;  from  which,  by  the  addition  of  hydrobromic  acid, 
we  obtain  trimethylene  bromide.  Eeplacing  the  bromine  atoms 
by  cyanogen  groups  we  produce  glutaric  nitrile,  and  this, 
on  reduction,  gives  us  pentamethylene  diamine.  On  dry 
distillation,  the  hydrochloride  loses  ammonium  chloride  and 
is  converted  into  piperidine,1  from  which  pyridine*  can  be 

1  Ladenburg,  Ber.,  1885,  18,  3100. 

*  Pyridine  was  obtained  in  a  bimpler  way  by  Kamsay  (Ber.,  1877,  10,  736) 


ii6      RECENT  ADVANCES   IN   ORGANIC  CHEMISTRY 


obtained  by  oxidation.  Pyridine  combines  with  methyl  iodide, 
and  when  the  pyridinium  methyl  iodide  thus  produced  is  heated 
to  about  300°  C.  it  suffers  intramolecular  change  and  is  con- 
verted into  the  hydriodide  of  a-picoline.  Picoline,  when  heated 
to  a  high  temperature  with  paraldehyde,  gives  a-propenyl- 
pyridine,  which,  on  reduction,  gives  isoconiine.1  On  further 
heating  to  300°,  or  boiling  with  solid  potash,  this  is  converted 
into  racemic  coniine.2  To  separate  the  right-  and  left-handed 
forms,  active  tartaric  acid  is  used,  since  this  substance  can  also 
be  obtained  synthetically  and  its  two  antipodes  can  be  separated 
from  each  other  by  means  of  the  sodium  ammonium  salt  with- 
out the  interposition  of  any  naturally  occurring  optically  active 
substance.  The  formulae  below  give  the  steps  which  we  have 
mentioned  — 


CH 


C-fS2->CS2->CCl4-> 


C:C1 


C:C1 


CH3 

CH.OH 

CH3 


CH2 
CH 
CH« 


CH2C1 
CHC1 


CH, 


CH2OH      CH2Br      CH2Br 


CH 

II 
CH, 


CH 


CH, 


I 
CH, 


CH. 


)H       COOH 
->    |          ->  CO   • 
Jla        CH3            | 
CH3 

CH2C1 

i 

CH2OH 

i 

CHC1   -> 
CH2C1 

CHOH    - 
1 
CH2OH 

XN"       CH2. 
->   CH2 

CH2.NH2 

CH2Br     CH2CN        CH2.CH2.NH2 


CH2    NH 

CHg CH2 


by  passing  a  mixture  of  acetylene  and  hydrocyanic  acid  through  a  heated  tube. 
Since  acetylene  is  produced  by  a  carbon  arc  in  a  hydrogen  atmosphere,  and 
hydrocyanic  acid  is  formed  by  sparking  a  mixture  of  acetylene  and  nitrogen, 
this  forms  a  simpler  synthesis  from  the  elements. 

1  Ladenburg,  Ber.,  1889,  22,  1403. 

2  Ibid.,  1906,  39,  2486. 


THE  ALKALOIDS  117 

CH2 

H2C         CH2 

I  | 

-CH:CH.CH3    ->    H2C        CH.CH2.  CH2.CH3 

N     < "  NH 

(d  +  Z)-Coniine  ->  d-  or  Z-Coniine. 

2.  Piperine. 

When  the  alkaloid  piperine  is  boiled  with  alcoholic  potash 
it  is  decomposed  into  piperidine  and  piperic  acid.1  The  consti- 
tution of  piperidine  is  established  by  the  Ladenburg  synthesis 
from  pentamethylene  diamine,  which  we  mentioned  in  connec- 
tion with  the  synthesis  of  coniine,  as  well  as  by  the  formation 
of  piperidine  from  pyridine,  by  reduction.  We  have,  therefore, 
only  to  determine  the  constitution  of  piperic  acid  in  order  to 
establish  the  constitution  of  piperine. 

The  decomposition  of  piperine  may  be  expressed  in  the 
following  way : — 

C17H1903N  +  H20  =  C6HuN  +  C12H1004 
Piperine.  Piperidine.    Piperic  acid. 

Fittig,  by  the  action  of  permanganate,  oxidized  piperic 
acid  to  an  aldehyde,  piperonal,2  which  has  the  composition 
C7H502 .  CHO.  On  further  oxidation,  piperonal  is  converted 
into  the  corresponding  acid,  piperonylic  acid,  C7H502 .  GOOH. 
Now,  this  substance  can  be  synthesized  by  the  action  of 
methylene  iodide  upon  protocatechuic  acid  in  presence  of 
caustic  potash,  and  therefore  it  must  be  the  methylene  ether 
of  that  acid. 


rrr  II  I  -  2HI 

±i 


C  H0n 

\I     HO— II      J— COOH  \0— 11      J— COOH 

Protocatechuic  acid.  Piperonylic  acid. 

By  subtracting   the  atoms  in  piperonylic  acid  from  those 
which  make  up  piperic  acid,  we  find  a  surplus  of  four  carbon 

1  Babo  and  Keller,  /.  pr.  Ch.,  1857,  72,  53. 

2  Fittig  and  Kemsen,  Annal&n,  1871,  159,  142. 


ii8      RECENT  ADVANCES  IN   ORGANIC  CHEMISTRY 

and  four  hydrogen  atoms.  This  —  C4H4  —  must  be  so  attached 
to  the  benzene  ring  of  piperonylic  acid  that  on  oxidation  it  dis- 
appears entirely  and  does  not  give  rise  to  a  second  carboxyl 
group  in  the  molecule.  The  only  way  in  which  this  condition 
can  be  fulfilled  is  by  inserting  the  group  —  GJIt  —  between 
the  carboxyl  group  and  the  benzene  ring  of  piperonylic  acid. 
Piperic  acid  would  thus  be  represented  by  — 


CH2 

\0—  II      J—  C4H4—  COOH 

When  piperic  acid  is  allowed  to  react  with  bromine,  it  takes 
up  four  atoms  of  the  halogen,  thus  showing  that  it  contains 
two  double  bonds.  These  double  bonds  must  be  in  the  side- 
chain  between  the  nucleus  and  the  carboxyl  group,  hence  we 
may  ascribe  the  following  formula  to  piperic  acid  :  — 


-CH  :  CH— CH  :  CH— COOH 

The  synthesis  of  piperic  acid  may  be  carried  out  in  the 
following  way.  Synthetic  protocatechuic  aldehyde l  was  con- 
verted by  methylene  iodide  and  potash  into  piperonal,2  which, 
when  warmed  with  acetaldehyde  and  very  dilute  alkali  (Claisen's 
reaction),  forms  piperonyl-acrolein — 


— CH:CH— CHO 

Piperonyl-acrolein. 

1  Tiemann  and  Koppe,  JBer.,  1881,  14,  2015, 

2  Wegscheider,  Monatsh.,  1893,  14,  382. 


THE   ALKALOIDS  119 

When  this  acrolein  derivative  is  heated  for  several  hours  with 
sodium  acetate  and  acetic  anhydride  it  condenses  with  a  molecule 
of  acetic  acid  (Perkin's  reaction),  and  forms  piperic  acid  1  — 


—  CH  :  CH—  CH  :  CH—  COOH 


By  converting  piperic  acid  into  its  chloride  and  heating  the 
latter  with  piperidine  in  benzene  solution,  piperine  is  formed.  2 


CH2-CH2 
CH2  / 

6-4      J—  CHiCH—  CH:CH—  CO.Cl     +     HN  CH2 


CH2— 

Piperic  acid  chloride.  Piperidine. 

UCH2-CH2 
/  \ 

— CH :  CH— CH :  CH— CO-  N  CHS 

\ 

Piperine. 

In  this  way  the  alkaloid  can  be  synthesized,  its  constitution 
being  proved  by  the  synthesis  and  further  certified  by  the 
decomposition  reactions  which  we  have  mentioned. 


3.  Trigonelline. 

This  alkaloid  has  the  composition  CvH^NOa.  It  was  dis- 
covered by  Jahns 3  in  1885 ;  and  in  the  following  year  its 
constitution  was  proved  by  Hantzsch,4  who  obtained  it 
unintentionally  in  the  course  of  an  examination  of  some 
derivatives  of  nicotinic  acid. 

1  Ladenburg  and  Scholtz,  Ber.,  1894,  27,  2958. 

2  Rugheimer,  Ber.,  1882, 15, 1390 ;  Fittig  and  Remsen,  Annalen,  1871, 159, 142. 

3  Jahns;  Ber.,  1885,  18,  2518. 

4  Hantzsch,  Ber.,  1886;  19,  31. 


120      RECENT  ADVANCES    IN   ORGANIC   CHEMISTRY 

Hantzsch  treated  nicotinic  acid  (I.)  with  caustic  potash  and 
methyl  iodide,  obtaining  the  methyl  ammonium  iodide  of 
nicotinic  methyl  ester  (II.).  When  this  is  acted  on  by  silver 
oxide  the  iodine  atom  is  exchanged  for  a  hydroxyl  group,  and 
the  compound  (III.)  is  produced,  which  at  once  loses  water  and 
is  converted  into  a  betaine  (IV.).  This  synthetic  body  was 
isomeric  with  trigonelline,  and  on  comparing  the  two  substances 
Jahns l  found  them  to  be  identical.  Trigonelline  is  therefore 
the  methyl-betaine  of  nicotinic  acid. 


— COOH  If     ^— COOCH 


Nicotinic  acid. 

(III.)  (IV.) 

>/\s. 

-COOH  |f    ^— CO 


CH3     OH  CH3 

Hydroxy-acid.  Betaine 

(Trigonelline). 

D. — THE  PYRROLIDINE  GROUP 
1.  Nicotine. 

The  alkaloid  nicotine  stands  in  a  position  midway  between 
the  pyridine  and  the  pyrrolidine  groups ;  for,  as  will  be  shown 
presently,  it  contains  both  a  pyridine  and  a  pyrrolidine 
nucleus.  It  therefore  forms  a  convenient  bridge  by  which  we 
can  pass  from  the  consideration  of  the  one  class  to  the  other. 

Nicotine  is  a  basic  substance  having  the  composition 
CioHuNfr  Its  constitution  has  been  established  by  means  of 
the  following  reactions : — 

1  Jahns,  Ber.,  1887;  20,  2840. 


THE  ALKALOIDS  121 

1.  Mtric  acid,  chromic  acid,  or  potassium   permanganate 
oxidize  nicotine l  to  nicotinic  acid — 


— COOH 


2.  By  the  action  of  bromine  upon  nicotine,  two  derivatives  2 
are  formed  — 


(a)  Dibromocotinine, 

(b)  Dibromoticonine, 

3.  When  dibromocotinine  is  decomposed  by  bases  it  gives 

methylamine,  oxalic  acid,  and  a  compound  C7H7NO. 
By  the  same  treatment  dibromoticonine  yields  methyl- 
amine, malonic  and  nicotinic  acids. 

4.  Nicotine  is    a  di-tertiary    base,3  giving    two    isomeric 

methyl  iodide  addition  products. 

From  the  first  reaction,  it  is  obvious  that  nicotine  must  be 
pyridine,  with  a  side-chain  in  the  j3-position. 


— C6HWN 


From  the  third  reaction  it  is  clear  that  of  the  two  nitrogen 
atoms  in  nicotine,  one  carries  a  methyl  group.  This  one 
cannot  be  the  pyridine  nitrogen.  Further,  the  second  nitrogen 
atom  (which  does  carry  the  methyl  radical)  cannot  belong  to 
a  pyridine  ring.  We  may  thus  go  a  step  further,  and  represent 
nicotine  by  the  formula — 


— C5H7:N.CH3 


1  Huber,  Annalen,  1867, 141,  271 ;  Weidel,  Annalen,  1873,  165,  328;  Laiblin, 
Ber.,  1877,  10,  2136. 

2  Pinner,  Per.,  1893,  26,  292. 

3  Pictet  and  Genequand,  Ber.,  1897,  SO,  2117. 


122      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 

Again,  the   third  reaction   shows  us  that  dibromocotinine 
and  dibromoticonine  give  rise  to  three  carbon  chains — 

i.  r 

C— CH2— C  — C.C—      , 

Malonic  acid  chain.        Oxalic  acid  chain.  C7H7NO  chain. 

These  must  be  somehow  combined  in  the  nicotine  molecule,  so 
we  may  write  the  nicotine  skeleton  thus — 

C— C 

-C    C 


\ 

To  this  we  must  attach  the  group :  N .  CH3  in  some  way.  From 
the  fourth  reaction  we  deduce  that  this  nitrogen  atom  is 
a  tertiary  one,  so  that  the  two  isomeric  methyl  iodide  addition 
products  may  be  explained  by  the  addition  of  methyl  iodide 
to  a  different  nitrogen  atom  in  each  case.  But  if  the  group 
:  N  .  CH3  is  to  contain  a  tertiary  nitrogen  atom,  and  also  to  be 
attached  to  the  nicotine  skeleton  given  above,  the  only  way  is 
to  make  the  nitrogen  atom  a  member  of  a  ring.  The 'con- 
stitution of  nicotine  would  then  be— 

OJtl 


The  synthetic  preparation  of  nicotine  proved  to  be  a  much 
harder  task  than  was  anticipated.  The  first  steps  were  taken 
by  Pictet  and  Crdpieux,1  who,  by  heating  /3-amido-pyridine  (I.) 
with  mucic  acid,  were  able  to  produce  (II.)  N-/3-pyridyl-pyrrol. 
Like  many  other  N-alkyl  derivatives  of  pyrrol,  this  substance 
when  passed  through  a  heated  tube  undergoes  a  molecular 
1  Pictet  and  Crepieux,  Per.,  1895,  28,  1904. 


THE  ALKALOIDS  123 

rearrangement,  in  the  course  of  which  the  pyridine  group  is 
transferred  to  the  carbon  atom  next  the  nitrogen  in  the  pyrrol 
ring.  The  compound  thus  formed  is  a/3-pyridyl-pyrrol  (III.). 

(III.) 
HC— CH 

/^        /  /^ 

NH, 


V 

0-amido-pyridine.          N-£-pyridyl-pyrrol.  0-pyridyl-a-pyrrol. 

From  this  substance  Pictet 1  continued  the  synthesis  in  the 
following  way.  The  a)3-pyridyl-pyrrol  forms  a  potassium  salt, 
the  imino-hydrogen  of  the  pyrrol  group  being  replaced  in  the 
usual  way  by  the  metallic  atom;  and  from  this  salt,  by  the 
action  of  methyl  iodide,  we  obtain  the  methyl  derivative  of 
the  iodomethylate  (IV.).  On  distillation  with  lime,  this  forms 
the  base  nicotyrine  (V.). 


(IV.)  (V.) 

HC— CH  HC— CH 

C    ^H 


Nicotyrine. 

Now,  this  body  cannot  be  reduced  direct  to  nicotine,  for  any 
agent  which  attacks  the  pyrrol  nucleus  will,  at  the  same  time, 
reduce  the  pyridine  ring.  The  transformation  can  be  carried 
out  in  the  following  way,  however.  The  nicotyrine  (V.)  is 
treated  with  iodine  in  alkaline  solution,  by  which  means  a 
mono-iodine  derivative  is  produced ;  it  in  turn  is  acted  on  by 
tin  and  hydrochloric  acid,  whereby  it  is  partially  reduced, 
forming  dihydro-nicotyrine  (VI.).  This  substance  reacts  with 
bromine  to  form  a  perbromide,  C5H4N .  C5H8N .  Br4,  which, 
by  reduction  with  tin  and  hydrochloric  acid,  yields  inactive 
nicotine  (VII.).  This  racemic  base  can,  like  coniine,  be  resolved 

>  Pictet,  C.  R.,  1903, 137,  860. 


124      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 


into  its  antipodes  by  means  of  tartaric  acid;  so  that  in  this 
way  the  synthesis  of  Isevo-nicotine,  corresponding  to  the  natural 
alkaloid,  can  be  accomplished. 


\ 


(VI) 
HC— CHa 

j 


CH5 


CH3 

Dihy  dronicoty  rin  e. 


(VII.) 
CH2  — 


—  CH      CH 


N 
OH 


Nicotine. 


2.  Tropidine. 

Hitherto  in  this  chapter  we  have  confined  our  attention  to 
substances  which  contain  a  single  ring  of  carbon  and  nitrogen 
atoms;  but  with  the  tropine  series  we  enter  a  new  class  in 
which  we  shall  have  to  deal  with  bridged  rings  analogous  to 
those  of  the  dicyclic  terpenes.  The  first  member  of  the  group 
we  are  about  to  examine  is  tropidine. 

Willstatter  has  succeeded  in  synthesizing  this  body  in  two 
ways,1  one  of  which  we  may  describe.  The  complete  synthesis 
is  made  up  of  two  distinct  stages,  in  the  first  of  which  cyclo- 
heptene  is  converted  into  cycloheptatriene ;  the  second  stage 
deals  with  the  formation  of  the  nitrogen  bridge  across  the  seven- 
membered  carbon  ring. 

Suberone,  the  starting  material,  is  obtainable  by  the  distil- 
lation of  the  calcium  salt  of  suberic  acid.  It  can  be  converted, 
by  reduction,  into  suberyl  alcohol,  and  hence  into  suberyl 
iodide,  which,  by  the  action  of  potash,  may  be  made  to  lose 
hydriodic  acid  and  yield  cycloheptene. 


CH 


(I.) 
-CH2— CO 

I 
CH, 


(II.) 
CH2— CH2— CH.OH 

CH2 

CH2 — CH2 — CH2 

Suberyl  alcohol. 

1  Willstatter,  Annalen,  1901,317,  268;  1903,  326,  1. 


CH2 — CH2 —  CH2 

Suberone. 


THE   ALKALOIDS 


125 


(III.) 
CH2— CH2— CH .  I 


j. 


CH2 CH2 CH2 

Subervl  iodide. 


(IV.) 
CH2— CH2— CH 

II 
CH 

CH2 — CH2 — CH2 

Cycloheptene. 


Bromine  is  now  allowed  to  act  upon  this,  forming  the 
dibromide  (V.);  from  which,  by  the  action  of  two  molecules 
of  dimethylamine,  hydrobromic  acid  is  removed,  a  dimethyl- 
amine  group  being  attached  to  the  ring  at  the  same  time. 
The  substance  (VI.)  is  thus  formed. 


(V.) 
CH2—  CH2 


CH.Br 
CH  .  Br 


(VI) 
CH2— CH2— CH .  N(CH3)2 .  HBr 


2  — 


CH 


CH2— CH 


2 


This  is  subjected  to  the  action  of  methyl  iodide,  and  the 
addition  compound  thus  formed  is  converted  into  a  hydroxide  of 
the  ammonium  base.  On  distillation,  this  body  splits  off  water 
and  trimethylamine,  breaking  down  into  cycloheptadiene  (VII.). 
By  a  repetition  of  the  same  process,  a  third  double  bond  is 
inserted  in  the  ring ;  or  the  same  result  may  be  attained  by 
adding  two  atoms  of  bromine  to  (VII.)  and  splitting  off  two 
molecules  of  hydrobromic  acid  by  means  of  quinoline.  In  any 
case  the  resulting  compound  has  the  constitution  of  (VIII.). 


(VII.) 
CH2— CH=CH 

CH 

II 
CH2—  CH2 — CH 

Cycloheptadiene. 


(VIII.) 
CH2— CH=CH 

AH 

CH=CH-CH 

Cycloheptatriene.    , 


Having  thus  obtained  cycloheptatriene,  we  must  turn  to 
the  second  stage  in  the  synthesis  and  examine  the  means  by 
which  the  ring  is  bridged.  By  the  action  of  one  molecule  of 
hydrobromic  acid  upon  the  compound  (VIII.)  we  obtain  the 
monohydrobromide  (IX.),  which  reacts  with  dimethylamine  at 


126      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 


ordinary  temperatures  to  give  dimethylamino-cycloheptadiene, 
which  is  identical  with  a-methyl-tropidine  (X.). 


(IX.) 

CH2— CHBr— CH 
CH 

CH2-CH==CH 

Monohydrobromide  of 
Cycloheptatriene. 


(X.) 
N(CH8), 

CHa— CH— CH 

II 
CH 

I 
2 — =C-H. 

a-Methyl-tropidine. 


When  acted  on  by  sodium  in  alcoholic  solution,  this  methyl- 
tropidine  takes  up  two  hydrogen  atoms,  and  is  converted  into 
a-methyl-tropane  (XI.).  The  action  of  bromine  in  acid  solu- 
tion gives  a  dibromide  (XII.),  which,  on  heating,  undergoes 
intramolecular  change  into  bromotropane-methylammonium 
bromide  (XIII.). 

N(CH8)2 

CH2— CH— CH2 

I 
CH2 

CH2— CH=CH 
(XL) 

o-Methyl-tropane. 


CH2— CH- 


CH2— CH 


-CH2 
CH2 

CHa— CHBr— CHBr 
(XII.) 

Dibromide. 

CH2 


CH3 

/ 

] 

sT—  CH3    C 

\           i 

Br 

CH2— CH CHBr 

(XIII.) 

By  the  action  of  caustic  potash  upon  this  last  substance, 
hydrobromic  acid  is  split  off  and  the  methyl  bromide  addition 
product  of  tropidine  (XIV.)  remains,  which  is  converted  into 


THE   ALKALOIDS 


127 


the  chloride  and  then  dry  distilled.     Tropidine  (XV.)  is  thus 
produced. 


CH2— CH OIL 


CH2— CH 


-CH, 


N— CH3    CH 


CH.-CH- 


-CH 


(XIV.) 


N— CH3    CH 

I  If 

CH2— CH CH 

Tropidine. 
(XV.) 


This  synthesis  leaves  very  little  doubt  as  to  the  constitu- 
tion of  tropidine.  At  first  sight  it  might  be  supposed  that  if 
the  intramolecular  change  which  converts  (XII.)  into  (XIII.) 
were  to  involve  the  other  bromine  atom  instead  of  the  one 
chosen  above,  a  different  product  would  be  obtained — 


/CH3 

Br— 1ST—  CH3 


CH5 


CHB 


Examination   will   show,   however,   that    this   is   identical 
with  (XIII.). 


3.  Tr opine,  ^-Tropine*  and  Tropinone. 

We  must  now  consider  the  question  of  the  synthesis  of 
tropine  from  tropidine.  This  cannot  be  directly  accomplished, 
but  is  attained  through  an  intermediate  product,  i//- tropine, 
which  is  stereo-isomeric  with  tropine.  The  method  is  as 
follows.1  Tropidine  is  heated  with  hydrobromic  acid  in  acetic 
acid  solution,  by  which  means  a-bromotropidine  hydrobromide 
(I.)  is  obtained.  When  the  solution  of  this  substance  is 
treated  with  ammonia  or  caustic  alkali,  bromotropane  (II.)  is 

*  The  Greek  ^  is  used  instead  of  the  word  "  pseudo."  Thus  ^-tropine 
represents  pseudo-tropine. 

1  Willstatter,  Ber.t  1901,  34,  3163;  Anndlen,  1903,  326,  23;  cf.  Einhorn, 
Ber.,  1891,  23,  2889. 


128      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 


precipitated.  On  heating  this  with  dilute  sulphuric  acid  above 
200°  C.,  the  bromine  atom  is  replaced  by  a  hydroxyl  group  and 
^-tropine  (III.)  results. 


(I.) 

'1TT             pTT 

( 

yH2 

._AL12                v-'JLL—  ~ 

H\ 

CH.Br 

B/ 

(II.) 

CH2— CH— 


-CH, 


OJtl2 OH Oxl2 

Bromotropidinehydrobromide. 

CH2— 


N.CH3      CH.Br 
CH2— CH CH2 


Bromotropane. 


(in.) 


-CH, 


N.CHo      CH.OH 


CH2— CH- 


-CH, 


^/-Tropine. 

The  isomerism  of  tropine  and  ^/-tropine  may  be  explained 
very  simply.  If  the  space  formula  of  a  compound  having  the 
constitution  of  tropine  be  built  up,  it  will  be  found  that  there 
are  two  possibilities  :  the  hydroxyl  and  the  methyl  groups  may 
lie  on  the  same  side  of  the  ring  as  in  (A),  or  on  opposite  sides 
as  in  (B)— 

(A)                                                      (B) 
CH2— OH CH2  CH2— CH CH2 


CH3 


/        c 


OH 


H 
CH2— CH CH, 


CHc 


H 


HO 
CH2 — CH CH2 


Now,  of  the  two,  tropine  is  the  labile  isomer,  so  that  while  we 
can  convert  it  at  will  into  ^/-tropine,  the  reverse  change  is  not 
possible  direct.  Willstatter  and  Iglauer,1  however,  have  been 
able  to  obtain  tropine  from  ^-tropine  by  an  indirect  method. 
They  oxidize  ^-tropine  to  tropinone — 

1  Willstatter  and  Iglauer,  Her.,  1900,  33,  1170. 


THE   ALKALOIDS  129 

2  —  OH  --  CH-? 

I  I 

N  .  CH3     CO 

I  I 

CH2—  CH  --  CH2 

Tropinone. 


and  from  this  ketone  they  obtain  tropine  itself  by  the  action  of 
zinc  dust  and  concentrated  hydriodic  acid  — 


CH2— CH 

N.CH3 
CH2 


CH2 

I 

CH  .  OH 


CH  --  CH  2 

Tropine. 


It  will  be  noticed  that  in  the  foregoing  paragraphs  we 
neglected  to  take  into  account  a  possible  alternative  formula 
for  bromo-tropane,  which,  if  correct,  would  invalidate  our 
conclusions  with  regard  to  the  constitutions  of  tropine  and 
tropinone.  The  formula  of  tropidine  is  given  below,  and  it  will 
be  seen  that  hydrobromic  acid  might  be  added  on  to  it  in  either 
of  two  ways  — 


/-ITT       r^TJ 

V^-ll2  V^Jtl  

-CH2 

V       ^7 

i 

N.CH3 

CH.Br(L) 

^R       PH              PH         ^  ^^' 

])H2  —  CH  

1 
-CH2 

jL\%        vyiJ.-111           '•-  V_/iA2           ^^  — 

1                                 1           ^                               ( 

N.CH3      CH 

1             II    \#a,       ( 

JH2—  CH  CH           <^ 

^H      PH 

CH2 

1 

I 

Tropidine.                                 "^ 

CH2     (II.) 

r 

^TT_      P.TT 

PTT    T^v 

Now,  the  tropinone  derived  from  formula  (II.)  would  have 
the  following  constitution — 


_CH CH2 

N.CH3      CH2 
OH,— CH CO 


K 


130      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

which  differs  from  the  tropinone  we  have  already  dealt  with 
(derived  from  (I.))  in  having  only  one  methylene  group  next 
the  carbonyl,  while  the  other  tropinone  has  two  methylene 
groups,  one  on  each  side  of  its  carbonyl  radical.  But  from  an 
examination  of  the  properties1  of  tropinone  obtained  from 
bromo-tropane,  as  already  described,  it  is  found  that  it  must 
have  two  methylene  groups  adjacent  to  its  carbonyl  radical. 
For  example,  it  forms  a  ^-isonitroso-compound  with  nitrous 
acid ;  benzaldehyde  condenses  with  it  to  form  a  d^-benzal 
compound ;  while  with  oxalic  ester  it  gives  tropinone-^-oxalic 
ester.  The  presence  of  the  group  — CH2 — CO — CH2 —  in 
tropinone  is  thus  established,  which  at  once  disproves  the 
possibility  that  tropinone  is  derived  from  a  bromo-tropane  of 
formula  (II.). 


4.  Tropic  Acid. 

By  the  synthesis  of  tropine  we  have  approached  that  of 
another  alkaloid,  atropine.  This  substance,  when  boiled  with 
baryta  water,  breaks  down  into  tropine  and  tropic  acid.  We 
have  thus  established  the  constitution  of  half  the  atropine 
molecule;  and  in  the  present  section  we  shall  deal  with  the 
constitution  of  the  other  half. 

Tropic  acid  has  been  synthesized  by  Ladenburg  and 
Eiigheimer.2  Acetophenone  is  treated  with  pentachloride  of 
phosphorus,  whereby  the  oxygen  atom  is  replaced  by  two 
chlorine  ones,  and  acetophenone  chloride  is  formed.  This  is 
allowed  to  react  with  potassium  cyanide  in  alcoholic  solution 
to  form  the  nitrile  of  atrolactinic  ethyl  ether  — 

CH3 
C6H5—  C—  OEt 


The  nitrile  is  then  hydrolyzed,  forming  the  acid.  When  this 
body  is  boiled  with  concentrated  hydrochloric  acid  it  loses 
alcohol,  and  is  converted  into  atropic  acid  — 

1  Willstatter,  Per.,  1897,  30,  2679. 

2  Ladenburg  and  Rugheimer,  Ber.,  1880,  13,  376,  2041. 


THE  ALKALOIDS  131 

CH2 

/ 

C6H5— C— COOH 

Hydrochloric  acid  then  attaches  itself  to  the  double  bond, 
yielding  ]3-hydrochloratropic  acid — 

CH2C1 
C6H5— OH .  COOH 

This  substance,  when  boiled  with  potassium  carbonate, 
exchanges  a  chlorine  atom  for  a  hydroxyl  group,  and  is 
converted  into  tropic  acid — 

CH2OH 


-CH— i 


C6H5— CH— COOH 

Tropic  acid. 

5.  Atropine. 

The  constitutions  of  the  two  halves  of  the  atropine  molecule 
have  now  been  established,  and  the  atropine  synthesis  can  be 
carried  out  by  treating  a  mixture  of  tropine  and  tropic  acid 
with  hydrochloric  acid  gas  in  the  usual  way.1  Atropine, 
therefore,  is  the  tropine  ester  of  tropic  acid,  and  it  must  have 
the  constitution  shown  by  the  following  formula : — 

CH2— CH CH2  CH2OH 

N.CH3     CH.O.  CO.CH.C6H5 

CH2— CH—     — CH2 

Atropine. 

The  synthesis  of  atropine  from  the  elements  may  be 
accomplished  in  the  following  steps.  Glycerine  is  obtained  by 
the  reactions  already  described  in  the  section  on  coniine,  and 
from  it  glutaric  acid  is  produced.  This  body,  by  the  electro- 
lysis of  the  sodium  salt  of  its  mono-ester,2  gives  suberic  acid, 
which  is  then  converted  into  tropine  by  the  method  we  have 
described  under  that  head.  With  regard  to  tropic  acid,  we 

1  Ladenburg,  Ber.,  1879,  12,  941 ;  1880,  13,  104. 

2  Crum  Brown  and  J.  Walker,  Annalen,  1891,  261,  119. 


132      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

may  start  from  acetylene,  which  can  be  produced  by  a  carbon 
arc  in  a  hydrogen  atmosphere.  On  the  one  hand,  we  can  convert 
the  acetylene  thus  obtained  into  ethylene,  ethyl- sulphuric  acid, 
alcohol,  acetic  acid,  and,  finally,  acetyl  chloride ;  while,  on  the 
other  hand,  we  can  polymerize  it  direct  to  benzene  by  passing 
it  through  a  red-hot  tube.  From  the  acetyl  chloride  and 
benzene  we  can  produce  acetophenone  by  the  Friedel- Crafts' 
reaction,  after  which  we  proceed  as  already  described  under 
tropic  acid. 

6.  Ecgonine. 

Tropinone  forms  salts  with  alkalis,  and  these,  by  treatment 
with  carbonic  acid  in  the  usual  way,  can  be  converted  into  the 
alkali  salts  of  carboxylic  acids.1  In  the  case  of  the  sodium 
salt,  it  is  suspended  in  ether,  and  carbon  dioxide  passed  through 
the  liquid  at  ordinary  temperatures;  the  resulting  product  is 
the  sodium  salt  of  tropinone  carboxylic  acid,  and  when  this  is 
reduced  with  sodium  amalgam  in  a  weakly  acid  solution  it 
yields  a  mixture  of  two  isomeric  bodies  having  the  same 
composition  as  ecgonine,  C8Hi4NO  .  CO  OH. 

The  two  isomers,  however,  differ  in  character.  The  one 
has  all  the  properties  of  ecgonine,  except  the  power  of  rotating 
the  plane  of  polarization ;  it  is  a  true  carboxylic  acid,  forming 
salts  and  esters,  it  also  possesses  a  free  hydroxyl  group,  and  can 
be  converted  into  esters  by  acids.  The  second  isomer,  on  the 
other  hand,  behaves  quite  differently.  It  possesses  no  free 
hydroxyl  group,  nor  can  it  be  esterified  by  the  ordinary 
methods.  An  explanation  of  the  formation  of  two  such 
substances  is  to  be  found  by  considering  the  character  of  the 
sodium  derivative  of  tropinone. 

It  is  well  known  that  the  sodium  salts  of  ketonic  bodies 
usually  exist  in  the  enolic  form,  so  that  we  should  incline  to 
write  the  formula  of  the  tropinone  sodium  salt  thus — 

CH2— CH CH 

I  II 

N— CH3     C— 0— Na 

CH2— CH—     -CH2 

1  Willstatter  and  Bode,  Ber.,  1900,  33,  411. 


THE   ALKALOIDS  133 

The  action  of  carbon  dioxide  upon  this  would  produce  a 
sodium  salt  whose  constitution  could  be  written — 

CH2— CH CH 

I  II 

N.CH3      C— 0— COONa 

CH2— CH-      -CH2 

This  body  forms  by  far  the  greater  proportion  of  the  reaction 
mixture,  but  since  the  sodium  salt  of  tropinone  exists  in  the 
keto-  as  well  as  in  the  enol-form,  part  of  the  end-product  will 
have  the  constitution  shown  below — 

CH2— CH CH .  Na  CH2— CH CH .  COONa 


CO 


2—  CH  --  CH 


A. 


CH3      CO 


CH2 — CH CH2  CH2 — CH CH2 

This  last  substance,  on  reduction,  would  give  us  the 
alcohol — 

CH2— CH CH .  COOH 

N.CH3     CH.OH 
— OH Cli2 

which  proves  to  be  racernic  ecgonine. 

7,  Cocaine. 

From  ecgonine,  cocaine  can  be  prepared  by  benzoylating  the 
alcohol  radical,  and  then  esterifying  the  carboxyl  group  with 
methyl  alcohol. 

CH2-CH-      -CH .  COOCH3 

1ST .  CH3     CH .  0 .  CO .  C6H5 

CH2— CH-      -CH2 

Cocaine. 


134      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 

E.  —  THE  QUINOLINE  GROUP 
1.  The  Constitution  of  Cinchonine. 

The  alkaloid  einchonine  has  the  composition  Ci9H220N2. 
The  oxygen  atom  forms  part  of  a  hydroxyl  group,  as  is  shown 
by  acetylation  ;  and  the  two  nitrogen  atoms  are  tertiary  ones. 

I.  When  einchonine  is  oxidized  by  means  of  chromic  acid 
and  sulphuric  acid  l  it  breaks  down  into  two  substances, 
cinchonic  acid  and  meroquinene,  in  accordance  with  the 
following  equation  :  — 


-f  30  =  Ci0H702N  +  C9H1502N 
Cinchonine.  Cinchonic        Meroquinene. 

acid. 

Cinchonic  acid  has  been  shown  to  be  a  quinoline  carboxylic 
acid  of  the  formula  — 

COOH 


so  that  einchonine  itself  must  be  a  y-quinoline  derivative. 

For  the  sake  of  convenience,  we  will  refer  to  the  two  halves 
of  the  einchonine  molecule  as  the  "  quinoline  half "  and  the 
"  second  half."  It  is  obvious  that  the  hydroxyl  group  which 
is  known  to  exist  in  the  einchonine  molecule  must  be  situated 
in  the  "  second  half"  ;  for  if  it  were  in  the  "quinoline  half"  it 
would  appear  in  cinchonic  acid.  We  may  therefore  formulate 
Cinchonine  in  the  following  way  :  — 


C10H15(OH)N 


Konigs,  Ber.,  1894,  27,  1501. 


THE   ALKALOIDS  135 

II.  Now,  when  cinchonine  is  oxidized  with  potassium 
permanganate1  instead  of  chromic  acid,  the  decomposition 
products  are  quite  different  from  those  obtained  before.  The 
reaction  takes  the  course  shown  below — 

Ci9H22ON2  +  40  =  Ci8H2003N2  +  H .  COOH 
Cinchonine.  Cinchotenine. 

This  new  oxidation  product,  cinchotenine,  contains  the  quino- 
line  nucleus  (as  is  shown  by  its  behaviour  on  further  oxidation). 
It  is  therefore  produced  by  a  decomposition  in.  the  "  second 
half"  of  the  molecule.  It  contains  a  hydroxyl  and  a  carboxyl 
group.  Cinchonine  can  take  up  one  molecule  of  a  halogen 
acid,  but  cinchotenine  has  lost  this  property.  Hence  the  group 
CH2  of  cinchonine  has  been  split  off,  leaving  the  carboxyl 
group  in  cinchotenine.  We  may  thus  carry  our  deductions  a 
step  further,  and  write  the  formula  of  cinchonine  in  the  follow- 
ing way : — 

/CH :  CH2 


III.  We  must  now  turn  to  a  different  reagent.  When 
cinchonine  is  treated  with  phosphorus  pentachloride  and  then 
with  alcoholic  potash  it  loses  a  molecule  of  water  and  is 
converted  into  cinchene 2 — 

C19H22ON2  -  H20  =  C19H20N2 
Cinchonine.  Cinchene. 

When  heated  with  twenty-five  per  cent,  phosphoric  acid,3 
cinchene  takes  up  two  molecules  of  water  and  is  decomposed 
into  lepidine  and  meroquinene — 

Ci9H20N2  +  2H20  =  C10H9N  +  C9H1502N 
Cinchene.  Lepidine.      Meroquinene. 

1  Konigs,  Annalen,  1879,  197,  374. 

2  Comstock  and  Konigs,  Per.,  1884,  17,  1985. 

3  Konigs,  Ber..  1890,  23,  2677;  1894,  27,  900. 


136      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 
Lepidine  is  known  to  have  the  formula — 
OH, 


IV.  Meroquinene  is  the  next  substance  whose  decomposi- 
tions must  be  examined.  When  it  is  oxidized  with  an  ice-cold 
mixture  of  sulphuric  acid  and  potassium  permanganate  it  gives 
cincholoiponic  acid 1 — 

C9H1502lSr  +  40  =  C8H130*N  +  H .  COOH 

Meroquinene.  Cincholoiponic 

acid. 

This,  by  the  action  of  aqueous  permanganate,  is  converted 
into  loiponic  acid 2 — 


[  +  02  =  C7Hn04N  +  H .  COOH 

Cincholoiponic  acid.      Loiponic  acid. 

Loiponic  acid  is  an  unstable  form  of  hexahydrocinchomeronic 
acid,  for  on  heating  with  caustic  potash  it  is  converted  into  that 
substance  by  isomeric  change.  By  assuming  the  structure  of 
loiponic  acid  to  be  the  same  as  that  of  hexahydrocinchomeronic 
acid  (the  configurations  of  the  two  being  different),  we  can 
work  back  step  by  step  to  meroquinene,  whose  formula  must 
therefore  be  that  shown  in  the  series  below — 

CH2.COOH  CH2.COOH 

I  I 

CH  CH 

H2C         CH.CH:CH2  H2C         CH .  COOH 

II  II 

H2C        CH2  H2C        CH2 

v  v 

Meroquinene.  Cincholoiponic  acid. 

1  Konigg,  Ber.,  1895,  28,  1986,  3150. 

2  Skraup,  Monatsh.,  1896,  17,  377;  Konigs,  Ber.,  1897,  80,  1329. 


THE  ALKALOIDS  137 

COOH 

A 

H2C        CH  .  COOH 

o 


NH 

Loiponic  acid. 

The  position  of  the  —  CH2  .  COOH  group  of  meroquinene 
is  uncertain. 

The  formula  above  is  due  to  Konigs,  but  the  alternative  put 
forward  by  Miller  and  Rohde  1  — 

CH3—  C—  COOH 

H2C         CH.CH:CH2    <, 

I          I 
H2C        CH2 

\   / 
NH 

has  probably  as  much  to  recommend  it. 

Of  the  ten  carbon  atoms  of  the  "second  half"  we  have  thus 
established  the  mode  of  linkage  of  eight:  five  in  a  piperidine 
ring,  two  in  a  vinyl  group,  and  one  in  a  methyl  or  methylene 
group.  The  ninth  carbon  atom  of  the  "second  half"  must  be 
utilized  in  joining  the  two  halves  together.  Thus  we  have  only 
to  determine  the  position  of  the  tenth  carbon  atom  of  the 
"second  half." 

V.  It  will  be  remembered  that  the  two  nitrogen  atoms 
of  cinchonine  are  tertiary;  but  it  has  been  shown  that  the 
nitrogen  atom  of  meroquinene  is  a  secondary  one.  This  has 
been  established  by  the  usual  reactions  of  the  imido-group,  and 
agrees  with  the  constitution  which  we  have  ascribed  to  mero- 
quinene in  the  previous  paragraph.  This  peculiar  behaviour 
of  the  nitrogen  atom  can  best  be  explained  by  the  assumption 
that  in  the  "second  half"  of  cinchonine  we  have  a  nucleus  of 
either  of  the  types  (I.)  or  (II.)  — 

1  Miller  and  Bolide,  Ber.,  1895,  28,  1060. 


138      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 


Konigs'  view. 
CH 


v.  Miller's  view. 
CHfl 


When  such  a  nucleus  as  (I.)  is  heated  with  dilute  acids  it 
will  undergo  intramolecular  change  into  an  imido-ketone  in  the 
way  expressed  by  the  formula  (la.)  below.  If  the  type  (II.) 
be  chosen  instead  of  (I.)  the  analogous  substance  (Ha.)  would 
be  produced  in  the  same  way. 


Such  a  change  actually  occurs  when  cinchonine  is  heated 
with  dilute  acetic  acid;  an  imido-ketone  results,  which,  on 
account  of  its  poisonous  properties,  is  named  "  cinchotoxine." l 
Thus  it  is  apparent  that  across  the  piperidine  ring  there  is  a 
bridge  of  one  carbon  atom,  and  this  accounts  for  the  missing 
tenth  carbon  atom  in  the  "  second  half "  of  cinchonine. 

From  the  foregoing  evidence,  cinchonine  would  be  repre- 
sented by  either  of  the  two  formulae  below — 

1  Miller  and  Bolide,  Ber.,  1894,  27,  1187,  1279;  1895,  28,  1056. 


THE   ALKALOIDS 


139 


H.CH:CH2 


N 


2.   5^6  Constitution  of  Quinine. 

Knowing  the  constitution  of  cinchonine,  we  can  easily  prove 
that  of  quinine. 

I.  Quinine   differs   from    cinchonine   by   one   carbon,   one 
oxygen,  and  two  hydrogen  atoms — 

CaoHaANa  -  Ci9H22ON2  =  CH20 
Quinine.  Cinchonine. 

This  points  to  quinine  being  a  methoxy-derivative  of  cincho- 
nine, if  we  bear  in  mind  the  similarity  in  character  between  the 
two  substances. 

II.  When   oxidized   with   sulphuric   and    chromic    acids,1 
quinine  gives  the  acid  (A) ;  whereas  it  will  be  remembered  that 
cinchonine  gave  cinchonic   acid  (B).     Meroquinene  is  one  of 
the  oxidation  products  in  both  cases. 

COOH  COOH 


— OCH3 


(A)  (B) 

III.  This  proves  the  presence  and  position  of  the  methoxyl 

1  Skraup,  Monatsh.,  1881, 2,  591 ;  1883, 4,  695 ;  1891, 12, 1106 ;  1895, 16, 2684. 


140      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

group  in  quinine ;  and  since  in  its  reactions  quinine  forms  an 
exceedingly  close  analogue  to  cinchonine,  we  are  justified  in  con- 
cluding that  it  is  a  methoxy-cinchonine  of  the  following  consti- 
tution (accepting  Konigs'  view  of  the  structure  of  cinchonine) : — 


CH2        CH .  CH :  CH2 
H2C  HO— CK  CH2 

^T^ 

CH, 

/^ 

OCH< 


Quinine. 

3.  CincJionidine  and  Gonchinine. 

Cinchonine  has  three  asymmetric  carbon  atoms  in  its  mole- 
cule, and  therefore  it  may  occur  in  several  stereoisomeric 
forms.  Cinchonidine  is  supposed  to  be  one  of  these ;  while 
conchinine  is  a  stereoisomer  of  quinine. 

F. — THE  ISOQUINOLINE  GROUP. 
1.  The  Constitution  of  Papaverine. 

The  constitution  of  papaverine  is  a  much  simpler  question 
than  that  with  which  we  have  just  dealt  in  the  case  of 
cinchonine.  There  are  six  steps  in  the  argument.1 

I.  In    the    first    place,    the    formula    of    papaverine    is 
C20H2i04N";   it  contains  four  methoxyl  groups,  which   can   be 
hydrolyzed,  yielding  the  substance  papaveroline,  Ci6H9N(OH)4. 
This  accounts  for  all  the  oxygen  atoms. 

II.  On  fusion  with  alkali,  papaverine  breaks  down  into  two 
nuclei,  one  of  which  contains  nitrogen,  while  the  other  nucleus 
is  nitrogen-free.     The  first  was  proved  to  be  a   dimethoxy- 
quinoline  of  the  constitution — 

1  Goldschmiedt,  Monatsh.,  1883,  4,  704 ;  1885,  6,  372,  667,  954 ;  1886,  7,  485 ; 
1667,  8,  510;  1888,  9,  42,  327,  3i9,  (579,  762,  778 ;  1889,  10,  673,  692. 


THE  ALKALOIDS 


141 


while    the     second    decomposition    product    was     dimethyl- 
hoinocatechol — 


CH«— 


— OCHc 
-OCH. 


III.  The  fact  that  these  two  groups  are  directly  united  to  one 
another  follows  from  the  composition  of  the  two  decomposition 
products — 

H2  +  CaoHaAN  =  CnHnOaN  +  C9H1202 

Papa  verm  e.        Dimethoxy-        Dimethoxy- 
quinoline.        homocatechol. 

IV.  We  must  now  examine  the  question  of  the  manner  in 
which  the  two  nuclei  are  united.     Since  papaverine  contains 
four  methoxy-groups,  and  each  of  the  decomposition  products 
contains  two,  it  is  obvious  that  during  the  decomposition  no 
methoxy-group  is  destroyed.     Now,  if  the   link  between  the 
two  nuclei  had  been  an  oxygen  atom,  i.e.  if  papaverine  had 
contained    the    grouping    K — 0 — CH2 — 0 — E,    then    in    the 
breakdown  of  the  molecule  one — 0  .  CH2 .  0 — group  would  have 
been  destroyed.     We  may  therefore  exclude  the  idea  of  joining 
the  two  nuclei  through  an  oxygen  atom,  and  must  assume  that 
they  are  directly  united,  carbon  to  carbon. 

V.  Our  next  problem  is  to  find  which  carbon  atom  of  the 
isoquinoline  ring  is  joined  to  the  other  nucleus.     When  we 
oxidize  papaverine  with   potassium   permanganate,  we  obtain 
a-carbocinchomeronic  acid — 


142      RECENT  ADVANCES   IN   ORGANIC  CHEMISTRY 


Hence  we  deduce  that  the  side-chain  (second  nucleus)  was 
attached  at  the  point  now  occupied  by  the  carboxyl  group, 
which  is  marked  with  an  asterisk.  Papaverine  is  therefore — 


VI. 


0,H6(OCH8)2 

We  have  now  to  settle  the  constitution  of  the 
group  — C7H5(OCH3)2.  This  must  be  the  dimethoxy-homo- 
catechol  radical,  which  has  the  same  composition.  We  have 
only  to  decide  whether  the  two  nuclei  are  joined  ring  to  ring 
or  by  the  intermediation  of  the  side-chain  of  the  dimethoxy- 
homocatechol.  Without  going  into  details,  it  may  be  said  that 
all  the  evidence  points  to  the  union  being  made  through  the 
side-chain.  The  constitution  of  papaverine  is  therefore — 


2.  The  Synthesis  of  Papaverine. 

The  synthesis  of  papaverine  has  recently  been  carried  out  by 
Pictet  and   Gams.1     The  reactions  may  be  grouped  in  five 


I.  The  first  step  in  the  process  is  the  synthesis  of  amino- 
aceto-veratrone.     For  this  purpose  veratrol  (I.)  is  treated  with 

1  Pictet  and  Gams,  G.E ,  1909, 149,  210. 


THE   ALKALOIDS  143 

acetyl  chloride  in  presence  of  aluminium  chloride,  whereby 
aceto-veratrone  (II.)  is  formed.  When  this  is  treated  with 
sodium  ethylate  and  amyl  nitrate,  it  yields  the  isonitroso- 
derivative  (III.),  which  can  then  be  reduced  by  tin  chloride 
and  hydrochloric  acid  to  the  hydrochloride  of  amino-aceto- 
veratrone  (IV.). 


CH30—  CH30—  X\-  CO—  CH3 


CH30- 

(III.)  (IV.) 

II.  We  must  now  turn  to  the  synthesis  of  homoveratroyl 
chloride.  Vanillin  (V.)  is  methylated  and  then  treated  with 
hydrocyanic  acid,  giving  dimethoxy-mandelic  nitrile  (VI.). 
When  this  is  boiled  with  hydriodic  acid  three  processes  take 
place  simultaneously;  reduction,  hydrolysis  and  the  splitting 
off  of  methyl  radicals.  We  thus  obtain  homoprotocatechuic 
acid  (VII.)  and  by  methylation  of  the  hydroxyl  groups 
followed  by  the  action  of  phosphorus  pentachloride  the  chloride 
of  homoveratric  acid  is  formed  (VIII.). 

CH30— /\,CHO  CH30— /  \CH(OH)  .ON 


HO— if     ^— CHo— COOH 


(VII.) 

III.  If  we   now  allow   the    amino-aceto-veratrone  hydro- 
chloride  obtained  in  Stage  I.  to  interact  with  the  homoveratric 


144      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 


chloride  of  Stage  II.  in  presence  of  alkali,  we  obtain  homo- 
veratroyl-amino-aceto-veratrone  (IX.), 


CH30- 
CH30— 


.CO.CH2.XH.CO.CH2. 


(IX.) 


IV.  An  inspection  of  the  formula  (IX.)  will  show  that 
though  the  substance  contains  two  carbonyl  groups,  one  of 
these  is  a  true  carbonyl  while  the  other  is  a  radical  which 
originally  formed  part  of  a  carboxyl  group.  When  the 
substance  is  reduced  with  sodium  amalgam  in  neutral  alcoholic 
solution,  the  true  carbonyl  is  reduced,  while  the  acidic  carbonyl 
remains  unaffected.  The  product  is  homoveratroyl-hydroxy- 
homoveratrylamine  (X.). 


CH30 


CH30- 


.  CH(OH) .  CH2 .  NH .  CO .  CH2 . 


(X) 


— OCH3 


— OCH< 


V.  When  this   substance  (X.)  is  treated  with   phosphorus 
pentoxide  in  boiling  xylene  solution,  it  loses  two    molecules 
of  water  and  is  converted  into  papaverine  (XL). 
OH 


CHa  -2H20  CH30- 
CH30— 


— OCH3 


THE   ALKALOIDS 


3.  The  Synthesis  of  Laudanosine. 

In  the  preceding  section  we  have  seen  how  the  synthesis 
of  papaverine  may  be  accomplished,  and  we  are  now  in  a 
position  to  consider  the  question  of  a  closely  related  alkaloid, 
laudanosine.  This  body  is  very  simply  produced  from  papa- 
verine. Pictet  and  Athanasescu 1  showed  that  if  we  form  the 
chloro-methyl  derivative  of  papaverine  and  then  reduce  this 
with  tin  and  hydrochloric  acid  we  obtain  methyl-tetrahydro- 
papaverine.  This  synthetic  substance  is  of  course  racemic ; 
and  from  it  the  dextro-antipode  was  obtained  in  the  usual  way 
by  making  the  quinic  acid  salt  of  the  alkaloid  and  fractionally 
crystallizing  it.  The  substance  thus  obtained  was  found  to  be 
identical  with  natural  laudanosine. 


— OCH3 


OCH3 

Papaverine. 


>CH3 

Laudanosine. 


Pictet  and  Finkelstein  2  have  recently  carried  out  the 
complete  synthesis  of  laudanosine,  but  as  the  method  is  very 
similar  to  that  which  we  have  already  described  in  the  case  of 
papaverine  we  need  not  enter  into  it  here. 

1  Pictet  and  Athanasescu,  Ber.,  1900,  33,  2346. 

2  Pictet  and  Finkelstein,  Ber.,  1909,  42,  1979;  C.  .R.,  1909, 148,  925. 

L 


146     RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

4.  Opianic  Acid. 

Though  opianic  acid  itself  is  not  an  alkaloid,  we  must  take 
up  its  constitution  at  this  point  owing  to  its  relation  with 
narcotine,  with  which  we  shall  deal  later. 

I.  When  narcotine  is    hydrolyzed   with    barium    hydrate 
or  sulphuric    acid,1    it    decomposes     into    opianic    acid    and 
hydrocotarnine — 

G22H23U7^N  -}-  H2O  —  CioHioOs     -f-     Oi2Hi5(J3^I 
Narcotine.  Opianic  acid.        Hydrocotarnine. 

II.  Opianic  acid  is  a  monobasic  acid,  and  therefore  we  may 
write  its  formula,  C9H903 .  COOH. 

III.  When  heated  with  hydriodic  acid,  two  methyl  groups  arc 
split  off  from  opianic  acid.2     It  therefore  contains  two  methoxy- 
groups,  and  may  be  written  thus,  (CH3O)2 .  C7H80  .  COOH. 

IV.  When  heated  with   potash3  it  gives   (by  reduction) 
meconine,  and  (by  oxidation)  hemipinic  acid — 

OCH3  OCH3 

CH30— f\— CO  v  CH30— /\— 

X0 

M>H, 

Meconine.  Hemipinic  acid. 

This  last  reaction  is  parallel  to  the  formation  of  benzyl  alcohol 
and  benzoic  acid  by  the  action  of  potash  upon  benzaldehyde,  so 
we  must  conclude  that  opianic  acid  contains  an  aldehydic 
group  ;  and  from  the  constitution  of  hemipinic  acid  it  is  obvious 
that  this  aldehyde  radical  must  be  next  the  carboxyl  group  of 
opianic  acid. 

V.  The  final  proof  of  the  presence  of  an  aldehyde  group  in 
opianic  acid  is  furnished  by  the  behaviour  of  its  sodium  salt 
when  distilled  with  soda-lime.4     Carbon  dioxide  is  split  off  in 
the  usual  way,  and  the  methyl  ether  of  vanillin  is  left.     The 
formula  of  opianic  acid  must  therefore  be  that  which  is  shown 
below — 

1  Beckett  and  Wright,  Trans.  Chem.  Soc.,  1875,  28,  583. 

2  Matthiessen  and  Foster,  Annalen  Suppl,  I.  333;  II.  378 ;  V.  333. 

3  Ibid.,  I.  332;  11.381. 

4  Beckett  and  Wright,  Trans.  Chem.  8oc.t  1875,  28,  583. 


THE   ALKALOIDS  147 

OCH3 


CHaO— f   \_COOH 


\— CHO  k       I1— CHO 

Opianic  acid.  Methyl  ether  of  vanillin. 

5.  The  Constitution  of  Cotarnine. 

The  next  stage  in  the  proof  of  the  narcotine  constitution  is 
reached  through  the  constitution  of  cotarnine.  This  substance l 
is  obtained  along  with  opianic  acid  when  narcotine  is  treated 
with  oxidizing  agents — 

C22H2307N  +  0  +  H20  =  Ci0H1005  +  C12H1504N 
Narcotine.  Opianic  acid.      Cotarnine. 

I.  Cotarnine  reacts  with  two  molecules  of  methyl  iodide, 
thus    proving    that    it    is   a   secondary  base.      The  reaction 
product  is  called  cotarnomethine  methyl  iodide,2  and  has  the 
composition  CiiHnO<iN(CH3)3I. 

II.  By  heating  this  body  with  caustic  soda,  trimethylamine 
is  split  off,3  and  cotarnone,  CnH1004,  remains.    This  proves  to  be 
an  aldehyde,  so  that  its  formula  can  be  written  Ci0H903  .  CHO. 

III.  When  cotarnone  is  oxidized  with  potassium  perman- 
ganate 4  it  gives  a  lactone,  cotarnolactone,  CnH1006,  from  which, 
on  further  oxidation,  cotarnic  acid,  CioH807,  is  obtained. 

IY.  By  the  usual  reactions  it  is  found  that  cotarnic  acid 5  is 
dibasic,  contains  a  methoxyl  radical,  and  has  its  carboxyl  groups 
in  the  ortho-position  to  one  another,  as  is  shown  by  the  ease 
with  which  it  forms  an  anhydride.  When  heated  with 
phosphorus  and  hydriodic  acid  to  about  160°  C.  it  yields  gallic 
acid — 

Wohler,  Annalen,  1844,  50, 1. 

Boser,  Annalen,  1888,  249,  157. 

Ibid.,  141. 

Hid.,  163. 

Ibid.,  163;  1899,  254,341. 


148      RECENT  ADVANCES  /Af   ORGANIC   CHEMISTRY 

OH 


HO-I      LCOOH 


V.  Now,    gallic   acid    differs   from   cotarnic   acid    by    the 
group  C3H202 — 


C10H807  -  C7H605      =      CH2      +      C0 
Cotarnic          Gallic          From  methoxy 
acid.  acid.  group. 


Part  of  this  we  can  account  for  by  the  loss  of  carbon  dioxide 
from  a  carboxyl  group,  since  cotarnic  acid  is  dibasic,  while 
gallic  acid  is  monobasic.  We  have  thus  one  carbon  atom  left 
unaccounted  for.  This  must  be  derived  from  the  methylene 
group  of  a  methylene  ether.  We  are  in  this  way  led  to 
formulate  cotarnic  acid  as  a  methyl-methylene-gallic-carboxylic 
acid,  C6H(OCH3)(CH202)(COOH)2.  For  such  a  substance  there 
are  only  two  possible  formulae — 


CH2— 0  OCH 


Without  going  into  details,1  we  may  say  that  the  general 
behaviour  of  the  substance  is  best  represented  by  (II.).  Cotarnic 
acid  therefore  has  the  constitution — 

OCH, 

COOH 

)— W      ]»— COOH 
Cotarnic  acid. 
1  Freuiid  and  Becker,  Her.,  1903,  36,  1521. 


THE   ALKALOIDS  149 

VI.  Cotarnolactone  must  therefore  have  the  formula — 

OCH3 


and  cotarnone  must  be — 

OCH3 


/o-f  VOHO 

CH2( 

\0— L      II— CH=CH2 


VII.  But  cotarnone  was  obtained  from  cotarnomethine 
methyl  iodide  and  soda,  whence  cotarnomethine  methyl  iodide 
must  have  the  structure — 

OCHg 

CH3 


CH2 

\0— L      J— CH2— CH2— N 


VIII.  Hence  cotarnine  should  have  the  following  constitu- 
tion ;  since  cotarnomethine  methyl  iodide  is  obtained  from  it 
by  the  action  of  two  molecules  of  methyl  iodide — 

OCH3 

n. 
-CHO 
-CH2— CH2-NH— CH3 

IX.  This  formula,  however,  fails  to  explain  the  formation 
of  a  pyridine  derivative,  apophyllenic  acid,  when  cotarnine  is 


ISO      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

oxidized  with  nitric  acid;1  and  to  account  for  this  we  must 
assume  that  the  free  aldehydic  group  has  disappeared  in  the 
course  of  some  intramolecular  ring-formation,  which  simul- 
taneously brings  into  existence  a  pyridine  chain  within  the 
molecule  of  cotarnine.  This  change  we  may  represent  in  two 
ways,  as  shown  in  the  formulae  below — 

OH 

OCH3   | 
OH 


OCH 


CHO 


c:  _ 

Cotarnine  (carbinol  form). 


OH 


2 

Cotarnine  (ammonium  form). 


It  is  generally  agreed  that  the  salts  of  cotarnine  are  best 
represented  as  derivatives  of  the  ammonium  form ;  for  instance, 
the  production  of  apophyllenic  acid  can  be  made  clear  on  this 
assumption — 


CH 

N03  /    \  „ 

Oxidize  HOOC— C  N/ 

I  \CH3 >  ||  I  XCH3 

CH2  HOOC— C          CH 

\  /  V/ 

CH2  CH 

Cotarnine  nitrate.  Apophyllenic  acid  derivative. 

1  Wohler,  Annalen,  1844,  50,  24. 


THE   ALKALOIDS  151 


With  regard  to  the  free  base,  however,  the  spectroscopic 
investigations  of  Dobbie,  Lauder  and  Tinkler l  have  shown  that 
the  structure  varies  with  the  solvent  in  which  the  substance  is 
dissolved.  In  ether  or  chloroform  the  carbinol  form  is  present ; 
but  the  addition  of  alcohol  to  the  solution  brings  into  existence 
the  ammonium  form;  in  pure  alcoholic  solution  no  less  than 
25  per  cent,  of  the  substance  is  present  as  ammonium  base. 


6.  The  Synthesis  of  Cotarnine. 

In  the  last  section  we  dealt  with  the  constitution  of  cotar- 
nine, and  we  must  now  take  up  the  synthesis  of  this  substance. 
Synthetic  cotarnine  has  been  prepared  by  Sal  way ; 2  but  as  the 
constitution  of  one  of  his  intermediate  products  is  left  doubtful 
in  the  synthesis,  it  is  not  possible  to  establish  the  cotarnine 
structure  from  his  work.  In  the  light  of  the  facts  given  in 
the  last  section,  however,  we  can  deduce  the  formulae  of  the 
intermediate  compounds. 

I,  The  first  stage  in  the  process  is  the  synthesis  of  j3-3- 
rnethoxy-4 :  5-methylenedioxy-phenyl-propionic  acid.  Salway 
took  as  his  starting-point  the  substance  myristicin — 


—  ff   ^—  CH2—  CH=CH2 


OCH3 


which  he  obtained  from  oil  of  nutmeg.  This  was  heated  with 
alcoholic  potash  to  convert  it  into  iso-myristicin ;  and  the  latter 
was  then  oxidized  to  myristicin  aldehyde  by  means  of  potassium 
permanganate — 

1  Dobbie,  Lauder  and  Tinkler,  Trans.  Chem.  Soc.,  1903,  83,  598. 

2  Salway,  Trans.  Chem.  Soc.,  1910,  97,  1208. 


152      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 


0— rf     \s-CH-CH— CH 


OCH3 

Isomyristicin. 


OCH3 

Myristicin  aldehyde. 


The  aldehyde  was  then  condensed  with  ethyl  acetate  by  means 
of  sodium,  and  the  resulting  ester  was  hydrolyzed  with  alco- 
holic potash — 


—OHIO    BQCH.COOC2H. 


OCH, 

,0—<f   ^— CH=CH— COOC2H5 
CH 


The  substituted  cinnamic  acid  thus  produced  was  reduced  with 
sodium  amalgam,  and  in  this  way  the  required  |3-3-methoxy- 
4  :  5-methylenedioxy-phenyl-propionic  acid  was  obtained. 


THE   ALKALOIDS  153 

— CH2— CH2— COOH 


II,  The  second  stage  ends  in  the  production  of  phenyl- 
acetyl-/3- 3- methoxy- 4  :  5-methylenedioxy-phenylethylamine. 
The  acid  (I.)  was  converted  into  the  amide  (II.)  in  the  usual 
way,  and  this  in  turn  was  changed  into  the  corresponding 
amine  (III.)  by  Hofmann's  reaction — 


,0— fl      NJ— CH2— CH2— CO— NH 
CH2 


— (f     ^— CH2— CH2— NH2 


The  phenylacetyl  derivative  (IV.)  was  then  prepared  by  the 
ordinary  method — 

— CH2— CH2— NH— CO— CH2— C6H5 

*3  (IV.) 

Phenylacetyl-)8-3-methoxy-4:5-methylenedioxy-phenyl-ethylamine. 

III.  This  phenylacetyl  derivative  was  condensed  by  heating 
it  with  phosphoric  oxide  in  presence  of  xylene ;  and  in  this  way 
a  mixture  of  two  isomeric  dihydro-isoquinoline  derivatives  was 
produced  (V.  and  VI.). 


154      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 


CH 


cnX 


— CH2— CHa— NH— CO— CH2— C6H5 

-^  (IV.) 


CH 


OCH, 


(VI.) 

IV.  The  substance  (V.)  is  8-methoxy-6 : 7-methylenedioxy- 
l-benzyl-3:4-dihydro-isoquinoline.  To  convert  it  into  cotar- 
nine,  it  is  necessary  in  the  first  instance  to  form  its  metho- 
chloride  (VII.),  which  is  then  reduced  by  means  of  tin  and 
hydrochloric  acid  to  1-benzyl-hydrocotarnine  (VIII.). 


CH2 


CH 


OCH 


(VII.) 


CH2.C6H5 


CH 
OCH3| 

CH2 .  CgHs 
(VIII.) 


Finally,  oxidation  with  manganese  dioxide  in  presence  of  sul- 
phuric acid  converted  the  benzyl  derivative  into  cotarnine. 


CH 


/ 


^0— 


CH2 


CH, 


NH .  CH3 
CHO 


OCH, 


THE  ALKALOIDS  155 

It  will  be  noticed  that  the  substance  (VI.),  if  treated  in  the 
same  way  as  (V.),  would  give  rise  to  an  iso-cotarnine ;  and  if 
the  cotarnine  constitution  were  unknown,  this  synthesis  would 
throw  no  light  upon  the  relative  positions  of  the  methoxy-group 
and  the  pyridine  ring. 


7.  The  Synthesis  of  Hydrocotarnine. 

On  reduction,  cotarnine  is  converted  into  hydrocotarnine,1 
which  is  formed  in  the  manner  indicated  by  the  formulae  below — 

OCH 

CHO 


CH2 

Alcohol. 

OCHg 

CH< 

^\   , 

,0-1 

CH2 

x    / 
CH2 

Hydrocotarnine. 

1  Beckett  and  Wright,   Trans.   Chem.  Soc.,  1875,  28,  577;  Bandow  and 
Wolffenstein,  Per.,  1898,  31,  1577. 


156      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 


8.  The  Constitution  of  Narcotine. 

We  have  now  in  the  course  of  the  previous  sections  amassed 
the  material  which  we  require  in  our  consideration  of  the 
narcotine  formula  ;  and  we  may  next  proceed  to  deal  with  the 
question. 

Narcotine  contains  no  carboxyl  or  hydroxyl  radical.  It  is 
made  up  of  one  hydrocotarnine  nucleus  and  one  opianic  acid 
nucleus,  the  latter  being  in  the  form  of  the  lac  tone,  meconine. 
This  is  shown  by  the  action  of  reducing  agents  upon  narcotine  — 


H2  =  C10H1004 
Narcotine.  Meconine.      Hydrocotarnine. 

We  must  now  consider  the  mode  of  linkage  of  these  two 
nuclei.  When  we  examine  the  formulae  of  meconine  and 
hydrocotarnine  — 


OCH3 

I         CH2 


N.CH 
CH2 


CH2 

Meconine.  Hydrocotarnine. 


it  is  obvious  that  the  linking  does  not  take  place  through 
an  oxygen  atom,  as  all  of  these  are  fully  occupied.  It  must, 
therefore,  occur  by  the  junction  of  two  carbon  atoms,  each 
of  which  loses  a  hydrogen  atom  in  the  union.  The  pair  of 
atoms  which  are  most  likely  to  be  concerned  in  the  linkage 
are  those  which  give  rise  to  the  aldehyde  groups  of  opianic 
acid  and  cotarnine,  so  that  the  formula  of  narcotine  would  be 
written — 


THE   ALKALOIDS  157 

OCH3 


CH30— 


N.CH3 


CH2 

Narcotine. 


9.  The  Syntheses  of  Gnoscopine  and  Narcotine. 

Perkin  and  Robinson l  showed  that  when  cotarnine  and  me- 
conine  are  boiled  in  alcoholic  solution  in  presence  of  potassium 
carbonate  the  substance  produced  is  identical  with  the  alka- 
loid gnoscopine ;  and  by  fractionally  crystallizing  the  d-bromo- 
camphorsulphonate  of  the  base 2  they  were  able  to  isolate  the 
dextro  and  fcevo  forms  of  narcotine,  gnoscopine  being  the  racemic 
variety.  The  laevo-narcotine  thus  obtained  was  identical  with 
the  natural  alkaloid. 


10.  The  Synthesis  of  Narceme. 


When  the  methyl  iodide  addition  product  of  narcotine  is 
treated  with  alkalis,  it  is  converted  into  a  substance  narcei'ne, 
which  was  first  called  pseudo-narceine.3  The  course  of  the 
reaction  may  be  formulated  in  the  following  way : — 

1  Perkin  and  Robinson,  Proc.  Chem.  800.,  1910,  26,  46. 

2  Perkin  and  Robinson,  ibid.,  131. 

3  Roser,  Annalen,  1888,  247,  167;  1889,  254,  357;  Freund  and  Frankforter, 
ibid.,  1893;  277,  31. 


158      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 

OCH3  OCH3 

I 
CH30-,/\-CO 


—OH/ 


0 


CH30 


KOH 

> 


\ 


0 


CH 


CH.O 


CH 


CH 


-/ 


0— 


N— CH3 

1 
CH 


,0— 


CHS 


N(CH3)2 
CH2 


CH2 

Narcotine  methyl  iodide. 


CH2 

Intermediate  product. 


OCH 


CH30 


CH 


^0— ^     A  CH 

CH2 

Intermediate  product. 


CH2— CH2— N(CH3)2 

Narceine. 


11.  The  Synthesis  of  Hydrastinine. 

This   substance,   which   occurs   among   the    decomposition 
products  of  the  alkaloid  hydrastine,  has  been  synthesized  by 


THE   ALKALOIDS  159 

Fritsch l ;  and  as  a  knowledge  of  its  constitution  may  help  us 
in  our  consideration  of  the  hydrastine  formula,  we  may  give 
a  brief  account  of  Fritsch' s  work  before  dealing  with  the 
natural  alkaloid. 

When  chloracetal  is  treated  with  ammonia,  it  yields  the 
substance  acetalamine,  which  has  the  formula — 

KH2.CH2.CH(OC2H5)2 

This  substance  can  be  made  to  condense  with  aromatic 
aldehydes;  and  when  the  products  thus  obtained  are  treated 
with  sulphuric  acid,  alcohol  is  split  off  and  isoquinoline 
derivatives  are  formed.  If  we  apply  this  reaction  to  the  case 
of  piperonal,  we  shall  have  the  following  series  of  reactions  : — 


CH 


,0— 


CHO     +     H2N .  CH2 .  CH(OC2H5)2 


V-L . 

Acetalamine. 
Piperonal. 

Q-f    ^-CHtN.CHa.CHCOCaHs),    +    H2O 

=  CH/ 

\0— « 

^V 

Piperonalacetalamine. 
CH 


/O—  (f      ^X  N  -2C2H5OH  \ 

[/  I  -      — ^  CH2( 

\o_il    JH      CH2  x< 


CH 


)H(OC2H5)2 

Piperonalacetalamine.  Methylenedihydroxyisoquinoline. 


When  the  methyl  iodide  addition  product  of  this  body  is 
reduced  by  means  of  tin  and  hydrochloric  acid,  it  gives  the 
substance  hydrohydrastinine — 

1  Fritsch,  Annalen,  1895,  286,  18. 


60      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 


OH 


CH 


\0-  CH 

^ 
CH 

lodomethylate. 


0- 


CH2 

Hydrohydrastinme. 

This  last  substance  Freund1  has  converted  into  hydrasti- 
nine by  oxidizing  it  with  potassium  bichromate  and  sulphuric 
acid. 

Now,  from  the  fact  that  the  behaviour  of  hydrastinine,  on 
reduction  and  salt  formation,  closely  resembles  that  of  cotarnine, 
we  are  enabled  to  put  forward  the  following  structural  formula 
for  it : — 

CHO 


NH.CH3 
CH2 


CH2 

Hydrastinine. 


CH2 

Hydrastinine  hydrochloride. 


This  formula  explains  why  hydrastinine  behaves  as  an  alde- 
hyde, why  it  forms  a  ring  compound  in  presence  of  acids,  why 
its  salts  contain  one  molecule  of  water  less  than  the  free  base, 
why  it  yields  apophyllenic  acid  on  oxidation,  and  many  other 
properties  which  the  substance  possesses.  A  comparison  of 
their  formulae  will  show  that  cotarnine  is  a  methoxylated 
hydrastinine. 

12.  The  Constitution  of  Hydrastine. 

Hydrastine  contains  one  methoxyl  group  less  than  narco- 
tine,  but  in  all  other  respects  it  resembles  that  compound. 
Now,  on  oxidation  with  dilute  nitric  acid,  hydrastine  breaks 
down  into  hydrastinine  and  opianic  acid  just  as  narcotine 
breaks  down  into  cotarnine  and  opianic  acid.  But,  as  was 
shown  in  the  preceding  section,  cotarnine  is  methoxy-hydrasti- 
nine,  so  that  we  may  conclude  that  if  we  eliminate  the 

1  Freund,  Ber.,  1887,  20,  2403. 


THE   ALKALOIDS  161 

inethoxy-group  from  narcotine  we  shall  have  hydrastine.  This 
actually  proves  to  be  the  case ;  so  that  we  may  write  the 
formula  of  hydrastine  by  simply  taking  that  of  narcotine  and 
replacing  the  methoxyl  radical  of  the  cotarnine  half  by  a 
hydrogen  atom.  Hydrastine  would  therefore  be — 

OCHg 

/\ 

CH30-(f     ^)- 


Hydrastine. 

G. — THE  PURINE*  GROUP. 
1.  The  Synthesis  of  Uric  Acid. 

The  problem  of  the  constitutions  of  the  purine  derivatives 
has  proved  one  of  the  most  complicated  chapters  in  the  recent 
history  of  organic  chemistry;  so  complicated  is  it  that  we 
cannot  devote  sufficient  space  to  allow  of  any  historical  treat- 
ment of  the  matter,  but  must  confine  ourselves  as  closely  as 
possible  to  the  actual  proofs  of  the  constitutions  of  some  of  the 
purine  series. 

The  most  important  member  of  the  group  is  uric  acid.  This 
substance l  has  been  synthesized  in  a  variety  of  ways ;  but  for 
the  most  part  the  syntheses  throw  no  very  clear  light  upon  the 

*  This,  like  many  other  chemical  terms,  is  what  Lewis  Carroll  defined  as  a 
portmanteau  word ;  it  is  derived  from  the  two  words  purum  uricum. 

1  Horbaczewski,  Monatsh.,  1882,  3,  796 ;  1885,  6,  356 ;  1887,  8,  201,  584 ; 
Behrend  and  Roosen,  Ber.,  1888,  21,  999 ;  Annalen,  1889,  251,  285 ;  Traube, 
Ber.,  1900,  33,  1371,  3035 ;  Fischer  and  Ach,  Ber.,  1895,  28,  2473;  Fischer,  Ber., 
1897,  30,  559. 

M 


162      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 

constitution  of  the  body.  We  may  describe  very  briefly  two  of 
these  synthetic  methods  of  preparing  uric  acid,  the  first  being 
due  to  Emil  Fischer  and  the  second  to  W.  Traube. 

When  malonic  acid  is  treated  with  urea,  it  yields  a  cyclic 
ureide.  malonyl-urea  or  barbituric  acid — 

NH2    HO— CO  NH— CO 

I  I  I 

CO  CH2    =   2H20   +  CO     CH2 

II  II 
NH2    HO— CO                           NH— CO 

Barbituric  acid. 

If  we  treat  barbituric  acid  with  nitrous  acid,  the  methylene 
group  is  replaced  by  the  isonitroso-radical  in  the  usual  way, 
giving  us  oximido-malonyl-urea,  which  is  also  called  violuric 
acid ;  and  on  reduction  of  this  substance  the  oximido-group  is 
converted  into  an  amido-radical,  producing  amido-malonyl  urea, 
or  uramil— 

NH— CO  NH— CO  NH— CO 

I  I  II 

CO     CH2  CO     C:NOH  CO     CH.NH2 


NH 


-CO  NH— CO  NH— CO 

Barbituric  acid.  Violuric  acid,  Uramil. 

On  treatment  with  potassium  cyanate,  uramil  takes  up  cyanic 
acid  and  is  changed  into  pseudo-uric  acid — 

NH— CO  NH— CO 

II  II 

CO     CH.NH2  CO     CH.NH.CO.NH2 

NH-CO  NH-CO 

Uramil.  Pseudo-uric  acid. 

It  is  very  hard  to  extract  water  from  pseudo-uric  acid,  but 
this  can  be  done  by  heating  it  with  molten  oxalic  acid  or  by 
boiling  it  with  hydrochloric  acid.  Under  these  circumstances 
one  molecule  of  water  is  lost  and  uric  acid  is  formed.  Uric 
acid  should  therefore  have  the  following  constitution : — 


THE   ALKALOIDS  163 

NH— CO 

CO     CH— NH\ 

I         I  /CO 

NH— C=N^ 

Its  property   of   forming  salts   could   be   ascribed   to   the 
existence  of  an  enolic  form,  such  as — 


HO 


N-C.OH 

.  C     C  -  N^ 

II      II 

N—  C  --  X 


It  is  more  usual,  however,  to  consider  uric  acid  to  exist  in 
the  isomeric  form  — 

NH—  CO 

CO     C-NHX 

I      ll         ;co 

NH—  C—  NH/ 

Uric  acid. 

The  second  synthesis  takes  as  its  starting-point  the  conden- 
sation of  urea  with  cyanacetic  acid,  which  takes  place  under  the 
influence  of  phosphorus  oxychloride  — 

NH2    HO—  C:0  NH—  CO 

CO  CH2  CO      CH2 

NH2  CN  NH2   CN 

Cyanacetyl-urea. 

Caustic  soda  causes  cyanacetyl-urea  to  undergo  an  intra- 
molecular change  by  which  it  is  converted  into  amido-uracil  — 

NH—  CO 

CO      CH 

I          II 
NH—  C—  NH2 

Aimdo-uracil. 


1 64      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

When  this  is  treated  with  nitrous  acid  it  gives  a  nitroso- 
compound  which  can  be  reduced  with  ammonium  sulphide  to 
diamido-uracil — 

NH— CO  NH— CO 

CO     C.NO  CO     C.NH2 

I!  I         II 

NH— C .  NH2  NH— C .  NH2 

Nitroso-eompound.  Diamido-uracil. 

The  next  step  is  to  treat  this  diamido-derivative  with  caustic 
potash  and  chloroformic  ester,  by  which  means  a  urethane  is 
formed — 

NH— CO  NH— CO 

I            |                 Cl.COOEt        I 
CO      C.NH2 >     CO     C.NH.COOEt 

I          II  I         II 

NH— C.NH2  NH— C.NH2 

Diamido-uracil.  Diamido-uracil  urethane. 

By  heating  the  sodium  salt  of  this  substance  to  180°-190°  C. 
we  obtain  the  sodium  salt  of  uric  acid. 

By  adapting  this  last  synthesis  we  can  obtain  many  uric 
acid  derivatives ;  for  we  may  use  substituted  ureas  instead  of 
the  parent  substance,  or  we  may  replace  the  urea  by  guanidine, 
or,  la&tly,  we  may  discard  the  chloroformic  ester  in  favour  of 
formic  ester. 

Before  leaving  the  question  of  uric  acid  we  must  glance  for 
a  moment  at  the  behaviour  of  that  substance  when  treated  with 
various  oxidizing  agents. 

"When  the  oxidation  is  carried  out  by  means  of  cold  nitric 
acid,  the  six-membered  ring  of  uric  acid  remains  intact,  while 
urea  is  split  off.  The  oxidized  ring  which  remains  can  be 
derived  from  mesoxalic  acid  and  urea ;  it  is  termed  alloxan,  or 
mesoxalyl-urea — 

NH— CO  NH— CO 

CO     C— NHV  CO     CO        H2NX 


;co  N;co 

NH— C( 


NH— C— NHX  NH— CO        H2N 

Uric  acid.  Alloxan.  Urea. 


THE  ALKALOIDS  165 

If,  on  the  other  hand,  we  use  alkaline  potassium  perman- 
ganate solution  as  our  oxidizing  agent,  the  five-membered  ring 
remains  unbroken,  while  the  six-membered  one  is  destroyed. 
The  first  products  in  this  case  are  two  substances,  uroxanic 
acid,  CsHsN^e,  and  oxonic  acid,  C^HsNaO*,  which  are  further 
oxidized  to  allantoin — 

NH2 

CO     CO— NHX 

I       I  >o 

NH— CH— NHX 

Allantoin. 

With  hydrogen  peroxide  the  sodium  salt  of  uric  acid  yields 
a  substance  of  the  formula  C^HaN^O^  tetracarbonimide,  which 
acts  as  a  weak  tetra-basic  acid ;  on  this  account  the  following 
formula  has  been  tentatively  ascribed  to  it : — 

NH— CO— NH 

I  I 

CO  CO 

NH— CO— NH 


2.  The  Synthesis  of  Theophylline. 

If  in  the  uric  acid  syntheses  we  substitute  symmetrical 
dimethyl-urea  for  the  parent  substance,  we  obtain  in  the  end 
dimethyl  uric  acid — 


CH3— N CO 

CO      C— NHX 
I         II          )CO 
CH3— N C— NHX 


When  this  is  treated  with  trichloride  and  oxy chloride  of 
phosphorus  at  150°  C.  it  is  converted  into  a  substance  chloro- 
theophyllin,  one  atom  of  chlorine  replacing  a  hydroxyl  group. 
Chlorotheophylline  must,  therefore,  have  the  following  con- 
stitution : — 


1 66      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 


CH.q— N CO 


CO      C— NH 

I          II 
CH3— N C— N^ 


XC.C1 


By  reducing  with  hydriodic  acid,  theophylline  l  is  formed  — 


CH3—  N  --  CO 

CO      C—  NIL 

I          II 
CH3—  N  --  C—  N 

Theophylline. 


3.  The  Synthesis  of  Caffeine. 

Caffeine  l  is  obtained  by  the  action  of  methyl  iodide  upon 
theophylline.  Its  constitution  is  therefore  expressed  by  — 

CH3—  N  --  CO 

CO      C—  Nr-CH3 

II         )CH 
CH3—  N  --  C—  1SK 
Caffeine. 

4.  The  Synthesis  of  Theobromine. 

If  we  take  as  a  starting-point  the  dimethyl  uric  acid  which 
has  the  constitution  (I.)  shown  below,  and  treat  it  with 
phosphorus  oxychloride,  we  shall  find  that  it  gives  chlorotheo- 
bromine  (II.),  which,  on  reduction  with  hydriodic  acid,  yields 
theobromine  (III.).2  The  reactions  are  parallel  to  those  which 
lead  from  the  isomeric  dimethyl  uric  acid  to  theophylline. 

' 


CO      0_N-CH3  ,0 

)co  i       ii         j.ci 

CH3-N.  _  C-NH  CH3-N-  -C-N^ 

(I.)  (II.) 

1  Fischer  and  Ach,  Her.,  1895,  28,  3135. 

2  Fischer,  Ser.,  1807,  30,  1839. 


THE   ALKALOIDS 


167 


NH-CO 
CO      C— 


N-CH3 


CH3—  N  --  C— 

Theobromine. 

(in.) 


5.  The  Synthesis  of  Purine. 

When  the  sodium  salt  of  uric  acid  is  treated  with 
oxychloride  of  phosphorus  it  yields  a  hydroxy-dichloro-purine 
of  the  following  formula  : — 

N=0.d 


Cl.C     C— NH 


;c .  OH 


N— C— N 


This,  by  means  of  trichloride  of  phosphorus,  can  be  changed 
into  a  trichloro-derivative,  the  third  hydroxyl  group  being 
replaced  by  a  chlorine  atom.  The  substance  thus  formed, 
trichloropurine,  is  then  treated  with  hydriodic  acid  at  0°  C. 
whereby  di-iodopurine  is  produced.  This,  by  reduction  with 
water  and  zinc  dust,  gives  purine  itself. 


01  .  C     C—  NH 


N—  C—  N 
Trichloropurine. 


N=C.I 

I      I 
I.C     C— NH 

)CH 

N— C— N 
Di-iodopurine. 


CH 


CH     C—  NH 

>H 

N  -  C—  N 
Purine. 


Purine  is  the  substance  to  which  all  the  substances  of  the 
purine  group  are  usually  referred;  the  derivatives  being  dis- 
tinguished by  means  of  the  system  of  numbering  shown  in  the 
following  scheme : — 


168      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

(1)            (6) 
N 0 

I             I        (7) 
(2)  C      (5)  C Nx 

I  I  >  (8) 

N 0 W 

(3)  (4)      (9) 

According  to  this,  the  substance  xanthine  is  2,  6-dihydroxy- 
purine  ;  theophylline  would  be  1,  3-dimethyl-xanthine ;  caffeine 
would  be  1,  3,  7-triinethyl-xau thine ;  theobromine  would  be 
3,  7-dimethyl-xanthine ;  and  uric  acid  8-hydroxy-xauthine. 


CHAPTER   VII 

THE    POLYPEPTIDES l 

WHEN  we  examine  the  contents  of  the  cells  from  which  living 
tissues  are  built  up,  we  find  that  they  are  for  the  most  part 
made  up  of  albuminous  bodies  of  extremely  complicated  chemical 
character.  These  albumins  are  distinguished  from  all  the  other 
naturally  occurring  substances  by  the  fact  that  animal  life  may 
be  supported  upon  them  alone  in  conjunction  with  water  and 
salt;  whereas  fats  and  carbohydrates  do  not  in  themselves 
furnish  nourishment  sufficient  for  the  support  of  animal  functions 
for  an  indefinite  period.  The  importance  of  the  albumins  from 
the  physiological  point  of  view,  therefore,  can  hardly  be  over- 
estimated; while  from  the  chemical  side  they  furnish  one  of 
the  most  difficult  and  complicated  problems  which  the  organic 
chemist  has  yet  attacked. 

The  difficulties  of  the  researches  which  have  been  carried 
out  in  this  branch  of  organic  chemistry  can  hardly  be  over- 
estimated. In  the  first  place,  many  albumins  are  non- 
crystalline  substances  which  require  special  treatment  before 
they  can  be  obtained  in  crystalline  form ;  this,  of  course,  makes 
it  very  difficult  to  determine  the  state  of  purity  of  any  specimen 
under  consideration.  Secondly,  the  extreme  sensitiveness  of 
albumins  to  heat,  acids,  or  alcohol  renders  them  very  liable  to 
be  altered  during  the  progress  of  the  ordinary  chemical  reactions. 
Again,  the  molecular  complication  of  these  substances  must  be 
tremendous,  if  we  are  to  judge  from  molecular  weight  determina- 
tions :  egg  albumin  has  been  estimated  to  have  a  molecular 

1  A  complete  set  of  references  up  to  1906  will  be  found  in  a  lecture  by 
Fischer  (Ber.,  1906,  39,  530).  See  also  Fischer,  Ber.,  1906,  39,  2893;  1907,  40 
1754,  3704 ;  1908,  41,  850,  2860 ;  Fischer  and  Konigs,  Ber.,  1907,  40,  2048 ; 
Fischer  and  Schulze,  ibid.,  943 ;  Fischer  and  Gerngross,  Ber.,  1909,  42,  1485 ; 
Fischer  and  Luiiiak,  ibiiL,  4752.  Fischer's  papers  have  been  reprinted  in  his 
book  " Die  Aminosauren,  Polypeptide  und  Proteine"  (1906). 


i;o      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 

weight  of  at  least  15,000,  according  to  the  results  of  the  freezing- 
point  method. 

In  the  foregoing  chapters  we  have  dealt  at  some  length 
with  the  constitutions  of  various  compounds,  and  it  will  be 
remembered  that  there  are  two  general  methods  of  investigating 
the  constitution  of  any  given  substance.  We  may  attack  the 
question  from  the  synthetical  side  or  from  the  analytical  point 
of  view:  in  the  first  case  we  study  the  general  properties 
of  the  substance,  then  ask  ourselves  in  what  way  we  can 
build  up  a  molecule  whose  reactions  will  resemble  those  of 
the  one  we  are  studying,  and  having  synthesized  this  body 
we  compare  its  reactions  with  those  of  the  original;  in  the 
analytical  method,  we  take  the  molecule  to  pieces  in  various 
ways,  and  isolate  a  series  of  decomposition  products,  from 
which  we  endeavour  to  guess  the  manner  in  which  they  were 
arranged  in  the  original  molecule.  Now,  in  the  case  of  the 
albumins,  the  first  line  of  research  turned  upon  the  analytical 
results.  This  was  to  be  foreseen,  for  it  seemed  almost  im- 
possible to  build  up  molecules  of  such  extreme  complexity. 
The  analytical  method,  however,  has  not  carried  us  very  far ; 
and  the  most  important  work  on  the  question  has  been  carried 
out  from  the  synthetical  side  since  Fischer  attacked  the  problem. 
Before  dealing  with  his  work,  however,  we  must  cast  a  glance 
at  the  decomposition  products  which  have  been  obtained  from 
the  albumin  group. 

The  oxidation  of  the  albumins  cannot  be  said  to  have 
yielded  results  of  any  great  interest;  the  greater  part  of  our 
knowledge  of  these  bodies  has  been  obtained  by  means  of 
hydrolysis  reactions.  When  ferments  are  allowed  to  act  upon 
protein  derivatives,  the  bodies  first  formed  are  albumoses  and 
peptones.  These  intermediate  compounds  can  be  further  broken 
down  into  amido-acids.  Hydrolysis  by  means  of  alkali  takes 
place  more  rapidly,  while  acids  decompose  the  albumins  most 
easily.  It  is  thus  made  clear  that  the  substances  lying  at  the 
base  of  the  albumins  belong  to  the  class  of  amido-acids ;  and, 
further,  that  these  acid  nuclei  are  linked  together  in  some  way 
which  allows  them  to  be  separated  one  from  another  by  means 
of  hydrolysis.  It  is  evident  that  amide-formation  is  the  most 
probable  method  of  uniting  the  nuclei ;  and  from  this  point  of 
view  Fischer  took  up  the  work  of  synthesizing  some  compounds 


THE  POLYPEPTIDES  171 

which,  while  not  themselves  of  the  protein  class,  would  show 
sufficient  resemblance  to  the  naturally  occurring  substances  to 
allow  us  to  deduce  the  probable  constitution  of  at  least  part  of 
the  albumin  molecule. 

To  describe  these  synthetic  substances,  Fischer  proposed  the 
name  "  Polypeptides"  by  which  he  intends  to  denote  those 
compounds  which  are  derived  from  two  amido-acid  molecules 
by  the  elimination  of  water.  A  few  polypeptides  have  been 
obtained  by  the  hydrolysis  of  proteins,  but  by  far  the  greater 
number  are  synthetic.  We  may  now  give  the  outlines  of  the 
methods  employed  by  Fischer  in  his  researches. 

In  the  first  place,  it  was  necessary  to  obtain  mono-amido- 
acids.  This  Fischer  did  by  means  of  the  ordinary  methods  — 
action  of  ammonia  on  the  esters  of  bromo-fatty  acids  or  by 
Strecker's  cyanhydrin  method  (addition  of  hydrocyanic  acid  and 
ammonia  to  an  aldehyde  and  hydrolysis  of  the  cyanhydrin  thus 
formed).  Now,  having  obtained  these  acids,  another  problem 
presents  itself.  If  we  combine  together  two  racemic  acids  we 
shall  have  not  a  single  reaction  product,  but  a  mixture  of  two 
new  racemic  substances.  For  instance,  if  we  start  with  racemic 
alanine  and  racemic  leucine,  we  should  produce  a  mixture  of 
the  four  isomers— 

d-Alanine-^-leucine.        c£-Alanine-/-leucine. 
£-Alanine-Z-leucine. 


The  two  substances  in  the  left-hand  column  then  combine  to 
form  a  racemic  substance,  and  the  two  in  the  right-hand  column 
to  form  another  racemic  compound,  so  that  we  should  have  two 
new  bodies  instead  of  a  pure  compound.  And,  of  course,  if  we 
coupled  together  more  than  two  racemic  acids  we  should  find 
the  number  of  stereo-isomers  in  the  product  increased  in  like 
manner.  This  evidently  threw  considerable  difficulty  in  the 
way,  and  to  avoid  it  Fischer  resolved  to  use  in  his  condensations 
optically  active  acids  only.  By  this  means  he  excluded  the 
possibility  of  racemic  compounds  being  formed,  so  that  from  one 
pair  of  amido-acids  he  obtained  only  a  single  reaction  product. 

This  did  not  clear  the  experimental  difficulties  away,  how- 
ever; it  only  carried  them  one  step  further  back.  For,  owing 
to  the  very  weak  acidity  of  the  amido-acids,  resolution  of  these 
substances  into  their  optically  active  antipodes  by  salt-formation 


i?2      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

with  active  bases  was  by  no  means  an  easy  task.  Fischer 
evaded  this  difficulty  in  turn  by  one  of  his  usual  simple  artifices. 
He  benzoylated  the  amido-group  of  the  acid,  and  thus  reduced 
its  basic  properties  to  a  minimum;  thereafter,  resolution  into 
the  optical  antipodes  presented  no  difficulty,  and  after  this  had 
been  accomplished,  the  benzoyl  radical  was  split  off  and  the 
optically  active  amido-acid  remained. 

I.  The  first  method  employed  by  Fischer  in  the  actual 
synthesis  of  polypeptides  depends  upon  the  elimination  of  a 
molecule  of  alcohol  from  two  molecules  of  amido-acid  ester  — 


.  CH2  .  COOEt  +  NH2  .  CH2  .  COOEt 


2  .       2  . 
=  NH2  .  CH2  .  CO  .  NH  .  CH2  .  COOEt  +  EtOH 

Now,  it  will  be  seen  at  once  that  if  we  applied  this  method 
as  given  above  to  a  mixture  of  two  different  amido-acid  s,  it  would 
be  sheer  chance  that  would  govern  the  production  of  the  end- 
product.  For  example,  if  we  were  to  combine  together  the  two 
esters  (A)  and  (B)  we  should  get  a  mixture  of  (C)  and  (D)  in  the 
reaction  product  — 

(A)    NH2.CH2.  COOEt 
*  (B)    NH2  .  CH  .  COOEt 

CH3 

(C)  NH2.CH2.  CO.  NH.CH.  COOEt 

CH3 

(D)  NH2.CH.  CO.  NH.CH2.  COOEt 

CH3 

This  difficulty  in  its  turn  was  overcome  by  Fischer  in  a  very 
simple  manner.  Before  condensing  the  two  substances  together 
he  allowed  one  of  them  to  react  with  ethyl  chlorocarbonate, 
which  acted  upon  the  amido-group  and  protected  it  from 
further  attack— 

Cl  .  COOEt  +  NH2  .  CH2  .  COOEt 

=  EtOOC  .  NH  .  CH2  .  COOEt  +  HC1 

When  a  compound  such  as  this  is  heated  for  thirty-six  hours 
with  the  ester  of  an  amido-acid,  alcohol  is  eliminated  between 
the  —  NH2  group  of  the  amido-acid  and  the  —  CH2  .  COOEt  group 


THE   POLYPEPTIDES  173 

of  the  above  substance,  whose  amido-group  cannot  react  in  this 
way.  Thus  we  know  at  once  the  constitution  of  the  resulting 
compound.  An  example  will  serve  to  make  the  matter  clear. 
If  we  start  with  the  substance  glycyl-glycine,*  and  treat  it  with 
chloro-carbonic  ester,  we  shall  obtain  the  substance  shown  below, 
glycyl-glycine  carboxylic  acid  ester — 

EtOOC .  01  +  NH2 .  CH2 .  CO  .  NH .  CH2 .  COOEt 

=  EtOOC .  NH .  CH2 .  CO .  NH .  CH2 .  COOEt  +  HC1 

When  this  substance  is  heated  for  thirty-six  hours  with 
leucine  ester,  ethyl  alcohol  is  eliminated  in  the  following 
way: — 

EtOOC.NH.CH2.CO.NH.CH2.COOEt+NH2.CH.(C4H9).COOEt 
=  EtOOC.NH.CH2.CO.NH.CH2.CO.NH.CH(C4H9).COOEt 

This  substance  is  the  carboxylic  ester  of  glycyl-glycine- 
leucine ;  as  can  be  seen  from  the  formulae,  it  can  have  no  other 
constitution  than  that  shown.  This  carbethoxy-glycylglycyl- 
leucine  ester  contains  three  amido-acid  nuclei,  and  is  therefore 
called  a  tri-peptide  derivative. 

II.  The  yields  of  end-product  from  the  foregoing  method  of 
synthesis  were  poor,  and  Fischer  therefore  turned  to  another  way 
of  attaining  his  objective.  When  the  ester  of  the  chlorocarbonic 
derivative  of  an  amido-acid  is  treated  with  thionyl  chloride,  an 
acid  chloride  is  formed ;  and  this  readily  condenses  with  amido- 
acid  esters,  forming  polypeptide  derivatives.  For  instance,  if  we 
start  again  with  the  derivative  obtained  by  the  action  of  chloro- 
carbonic ester  upon  glycylglycine,  and  treat  it  with  thionyl 
chloride,  we  shall  produce  the  chloride  whose  constitution  is 
shown  below — 

EtOOC .  NH .  CH2 .  CO  .  NH .  CH2 .  CO .  Cl 
When  this  chloride  is  condensed  with  glycylglycine  ester — 
NH2 .  CH2 .  CO  .  NH  .  CH2 .  COOEt 

it  yields  the  tetra-peptide  derivative,  glycylglycylglycylglycine- 
carbethoxy-ester — 

EtOOC.NH.CH2.CO.NH.CH2.CO.NH.CH2.CO.NH.CH2.COOEt 

*  Fischer  terms  "glycyl"  the  radical  NH2.CH2.CO—  which   is  derived 
from  glycine  (glycocoll)  NH2 .  CH2 .  COOH, 


174      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

III.  The  drawback  of  the  two  foregoing  methods  lies  in 
the    fact    that   so   far  no   method    has    been   discovered    by 
means  of  which  we  can  eliminate  the  group  — COOEt,  which 
is  attached   to   one  end   of  the   polypeptide   chain;    so   that 
neither  method  can  be  employed  to  build  up  a  true  polypeptide. 
Fischer  therefore  devised  another  method  by  means  of  which 
the  polypeptides  themselves  can  be  produced.     Starting  from 
the  ester  of  a  substance  like  glycine  (I.)  or  glycylglycine,  he 
treated  this  with  chloracetyl  chloride  (II.)  or  some  similar  com- 
pound.   Hydrochloric  acid  is  eliminated,  and  the  two  molecules 
combine  together  to  form  a  compound  with  chlorine  at  one  end 
of  the  chain  (III.)-     The  ester  group  at  the  other  end  of  the 
chain   is   then   hydrolyzed   very  carefully,  and   a   chloro-acid 
produced  (IV.),  which,  on  treatment  with  ammonia,  yields  a  true 
polypeptide  (V.) — 

(I.)  NH2.CH2.  COOEt 

(II.)  C1.CH2.CO.C1 
(III.)  01 .  CH2 .  CO  .  NH  .  CH2.COOEt 
(IV.)  01 .  CH2 .  CO  .  NH  .  CH2 .  COOH 

(V.)  NH2 .  CH2 .  CO  .  NH .  CH2 .  COOH 

The  reason  for  hydrolyzing  the  ester  (III.)  to  the  acid  (IV.) 
lies  in  the  fact  that  if  this  were  not  done  an  amide  would  be 
formed  on  treatment  with  ammonia,  and  the  amido  group  would 
be  most  difficult  to  get  rid  of  later. 

IV.  A  variation  of  the  previous  method  may  also  be  used. 
If  we  take  the  substance — 

Cl .  CH2 .  CO  .  NH  .  CH2 .  COOH 

which  was  formed  in  the  course  of  the  last  synthesis  we 
described,  and  treat  it  with  pentachloride  of  phosphorus,  we 
convert  the  acid  into  the  chloride  * — 

Cl .  CH2 .  CO  .  NH .  CH2 .  CO  .  Cl 

which  can  then  be  made  to  interact  with  glycine  ester,  yielding 
the  more  complicated  substance — 

Cl .  CH2 .  CO  .  NH  .  CH2 .  CO  .  NH  .  CH2 .  COOEt 

*  Thionyl  chloride  is  a  better  reagent  than  phosphorus  pentachloride  for 
producing  acid  chlorides.    The  reaction  takes  place  according  to  the  equation — 

K  .  COOH  +  SOC12  =  K .  CO .  Cl  +  S02  +  HC1 

from  which  it  will  be  clear  that  the  acid  chloride  can  be  obtained  pure  simply 
by  boiling  off  the  sulphur  dioxide  and  hydrochloric  acid. 


THE  POLYPEPTIDES  175 

The  remaining  chlorine  atom  may  then  be  replaced  by  the 
amido-group  by  means  of  ammonia ;  and  after  hydrolysis  of  the 
ester  group  the  tri-peptide  glycylglycylglycine  is  formed — 

NH2 .  CH2 .  CO  .  NH  .  CH2 .  CO  .  NH  .  CH2 .  COOH 

V.  This  modification  has   been   farther   extended.     When 
amido-acids  are  treated  with  a  mixture  of  acetyl  chloride  and 
phosphorus  pentachloride,  the  corresponding  acid  chlorides  are 
formed.    These  can  be  combined  with  other  amido-acids,  and  in 
this  way  we  can  obtain  polypeptides.     For  instance,  if  we  take 
glycine  and  treat  it  as  described  we  should  expect  to  produce 
glycyl  chloride — 

NH2.CH2.COOH    ->    NH2 .  CH2 .  CO  .  Cl 

This  can  be  condensed  with  another  molecule  of  glycine, 
forming  glycylglycine — 

NH2 .  CH2 .  CO .  01  +  NH2 .  CH2 .  COOH 

=  NH2 .  CH2 .  CO .  NH .  CH2 .  COOH 

VI.  If  we  abstract  two  molecules  of  alcohol  from  two  mole- 
cules of  an  a-amido-ester,  a  cyclic  substance  is  produced,  which 
is  a  derivative  of  ay-diketo-piperazine — 

CH2— NH2  EtO— CO  CH2— NH— CO 

+  =       |  +  2EtOH 

CO— OEt  H2N— CH2  CO — NH— CH2 

This  cyclic  compound,  when  carefully  treated  with  hydro- 
chloric acid,  can  be  opened  out  into  an  open-chain  body, 
glycylglycine — 

CH2— NH— CO  CH2— NH2  COOH 

I  |        +H20=      |  | 

CO — NH— CH2  CO — NH— CH2 

By  choosing  the  appropriate  amido-ester  from  which  to  start, 
a  given  polypeptide  may  be  obtained  in  this  manner. 

We  cannot  go  into  details  with  regard  to  the  various 
substances  which  have  been  synthesized  by  means  of  the 
foregoing  methods,  but  there  is  one  substance  which  is  worthy 
of  mention.  Fischer  has  recently  synthesized  an  octadeca- 
peptide  in  the  following  manner.  Starting  from  dextro- 
a-bromo-isocapronyl-diglycylglycine — 


176      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 
Br  .  CH  .  CO  .  (NH  .  CH2  .  C0)2  .  NH  .  CH2  .  COOH 


he  treated  this  according  to  the  fourth  method,  combining  it 
with  pen  ta-glycylgly  cine,  and,  finally,  exchanging  the  bromine 
atom  for  an  amido-group,  he  obtained  Isevo-leucyl-octaglycyl- 
glycine  — 

NH2  .  CH  .  CO  .  (NH  .  CH2  .  C0)8  .  NH  .  CH2  .  COOH 


This  polypeptide  was  then  coupled  with  dextro-bromo-iso- 
caproyl-diglycylglycine,  and  again  treated  with  ammonia, 
whereby  the  tetradecapeptide  shown  below  was  formed  — 


NH2.CH.CO.(NH.CH2.CO)3.NH.CH.CO.(NH.CH2.CO)8.NH.CH2.COOH 

C4H9 
Lasvo-leucyl-triglycyl-laevo-lucyl-octaglycyl-glycine. 


AH 

C4H9 


By  a  repetition  of  this  series  of  reactions  the  octadecapep- 
tide  was  formed,  which  has  the  constitution  shown  below — 

NH2.CH(C4H9).CO.(NH.CH2.CO)3.NH.CH(C4H9).CO.(NH.CH2.CO)3.NH 

HOOC.CH2.NH.(CO.CH2.NH)8.CO.CH.C4H9 

Z-Leucyl-triglycyl-Meucyl-triglycyl-Meucyl-octaglycyl-glycine. 

This  extraordinary  substance  is  apparently  one  of  the  most 
complicated  systems  of  known  constitution  which  has  hitherto 
been  synthesized.  Its  molecular  weight  is  twelve  hundred  and 
thirteen;  while  that  of  the  fairly  complicated  natural  body, 
tri-stearin,  is  only  eight  hundred  and  ninety-one. 

We  must  now  briefly  summarize  the  main  characteristics  of 
the  polypeptide  class,  and  it  may  be  of  interest  to  compare  them 
with  those  of  the  naturally  occurring  proteins.  The  polypep- 
tides  are  solids,  which  usually  melt  at  about  200°  C.,  with  some 
decomposition.  They  are  easily  soluble  in  water,  but  insoluble 
in  alcohol,  like  some  of  the  albumins ;  and  instead  of  having 
the  usual  insipid  or  sweet  taste  of  the  ordinary  amido-acid, 
they  are  bitter,  like  the  protein  derivatives.  In  dilute  sulphuric 
acid  solution  they  are  precipitated  by  phosphotungstic  acid, 
in  which  behaviour  they  resemble  the  albumins.  Both  the 
natural  and  artificial  classes  give  the  biuret  reaction.  The 


THE   POLYPEPTIDES  177 

action  of  ferments,  or  of  acids  or  alkalis,  is  the  same  in  both 
classes;  and  similar  products  are  obtained  when  animals  are 
fed  with  polypeptides  and  albumins.  In  the  case  of  ferment 
action  it  is  found  that  much  depends  upon  the  groups  which 
have  been  used  in  building  up  the  polypeptide  structure,  some 
polypeptides  being  much  more  easily  fermented  than  others. 

From  these  data  it  will  be  obvious  that  the  researches  of 
Fischer  and  Curtius  have  carried  us  into  a  series  of  substances 
which,  in  many  respects,  resemble  the  natural  bodies  of  the 
protein  class ;  how  far  the  parallel  holds  good,  and  how  high  in 
the  scale  we  can  carry  our  syntheses  remains  for  the  future  to 
make  clear. 


CHAPTEE  VIII 

%          THE   POLYKETIDES  AND   THEIR   DERIVATIVES 

BROADLY  speaking,  plants  differ  from  animals  in  that  they  can 
nourish  themselves  with  water  and  carbon  dioxide  alone,  while 
"the  animal  kingdom  requires  the  intermediation  of  vegetables 
and  other  organized  matter.  The  substances  which  lie  at  the 
base  of  all  syntheses  of  organized  tissues  must  therefore  be 
simple  compounds  of  carbon,  hydrogen,  and  oxygen.  Once 
having  synthesized  such  substances,  the  plant,  as  will  be  shown 
later  in  this  chapter,  could  easily  build  up  derivatives  of  the 
aliphatic,  aromatic,  and  heterocyclic  series. 

Given  formaldehyde,  sugars  may  be  produced  by  the  action 
of  alkalis ;  and  many  such  examples  of  the  production  of  com- 
plicated natural  bodies  from  very  simple  substances  are  known. 
In  the  present  chapter  we  shall  confine  ourselves  to  deriva- 
tives of  one  class ;  but  as  this  class  is  interwoven  with  all  the 
main  groups  of  organic  compounds,  it  will  serve  as  a  skeleton 
from  which  the  relations  between  apparently  quite  dissimilar 
groups  can  be  deduced.  At  the  same  time  it  must  be  borne  in 
mind  that  our  laboratory  synthetic  methods  differ  in  the  main 
from  those  employed  in  the  living  plant.  While  we,  in  our 
syntheses,  start  from  the  same  elements  as  the  plant  does,  we 
usually  build  up  our  substances  step  by  step,  proceeding  from 
simple  to  complex.  The  plant  appears  to  act  differently ;  for 
it,  apparently  by  condensation,  polymerization,  or  some  such 
process,  converts  its  simple  starting  substance  into  an  extremely 
complicated  derivative,  which  then  decomposes,  yielding  those 
products  which  have  been  identified  in  saps  and  tissues.  Again, 
while  most  of  our  ordinary  laboratory  reactions  can  be  applied 
to  the  production  of  substances  which  are  found  in  plants,  it  is 
obvious  that  the  plant  must  obtain  the  same  result  in  a  much 
simpler  manner.  For  instance,  when  we  wish  to  attach  side- 
chains  to  a  benzene  nucleus,  we  employ  aluminium  chloride  in 


THE   POLYKETIDES  AND    THEIR   DERIVATIVES     179 

the  Friedel-Crafts  reaction  ;  but  such  a  reagent  could  not  exist 
in  a  plant.  Further,  a  great  number  of  our  laboratory  reactions 
require  the  use  of  high  temperatures,  which  would  be  fatal  to 
plant-life. 

When  we  examine  the  compounds  known  to  us  in  the 
domain  of  organic  chemistry,  it  is  inconvenient  for  our  present 
purpose  to  regard  them  from  the  point  of  view  of  text-book 
classification.  What  is  of  chief  importance  to  us  is  the  ques- 
tion, Can  they  be  made  to  react  easily  ?  From  this  point  of 
view  we  divide  compounds  at  once  into  two  groups,  the  satu- 
rated and  the  unsaturated,  the  latter  being  the  reactive  ones. 
This  is,  of  course,  speaking  in  very  general  terms,  for  many 
saturated  substances  are  quite  reactive.  Now,  among  un- 
saturated substances  we  can  again  distinguish  two  classes — the 
desmotropic  and  the  non-desmotropic.  Of  these,  the  desmo- 
tropic  class  is  by  far  the  most  reactive.  The  cause  of  this  is 
obvious,  for  if  a  non-desmotropic  substance  be  brought  into  the 
presence  of  a  reagent,  it  has  only  one  way  in  which  it  can  react, 
and  if  combination  does  not  take  place  the  matter  ends ;  with 
a  desmotropic  compound,  however,  if  the  first  form  fails  to 
attack  the  reagent,  there  is  always  the  possibility  that  the 
second  form  may  be  more  successful. 

In  nature,  we  find  many  desmotropic  and  tautomeric  sub- 
stances ;  but  the  preponderating  class  is  that  which  contains 
compounds  of  the  type 

E—  CO— CH2— K'     ->      K—  C(OH)  :  CH— K' 

This  "keto-enol"  type  is  very  widely  distributed  among 
naturally  occurring  substances ;  it  is  found  in  nearly  every 
important  class  of  compounds,  from  the  purine  group  to  the 
terpenes  ;  and,  further,  its  one  form  is  converted  into  the  other 
isomeride  more  easily  than  is  the  case  with  practically  any 
other  mode  of  isomeric  change. 

The  simplest  member  of  the  class  of  substances  containing 
this  atomic  grouping  is  the  compound  keten,  which  has  the 
formula — 

CH2  :  CO 

As  will  be  seen  later,  this  group  of  five  atoms  is  capable  of 
polymerizing  or  condensing  with  other  compounds  in  many 


i8o      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

ways;  and  as  some  general  name  is  required  for  the  whole 
series,  we  shall  adopt  the  proposal  of  Collie,1  and  designate  as 
"  Polyketides  "  those  substances  which  are  obtained  by  the  poly- 
merization of  keten,  and  subsequent  addition  of  other  atoms. 
For  example,  acetic  acid,  H .  CH2 .  CO .  OH,  which  is  derived 
from  keten  by  the  addition  of  water,  would  be  termed  a  "  mono- 
ketide  ";  while  acetoacetic  acid,  H  .  CH2 .  CO  .  CH2 .  CO  .  OH, 
would  be  a  "  di-Jcetide." 

The  rest  of  this  chapter  will  be  devoted  to  the  discussion 
of  these  classes  of  compounds.  In  the  first  place,  a  rapid 
survey  of  the  general  relations  of  the  group  to  the  rest  of 
organic  compounds  will  be  given,  after  which  the  reactions  and 
properties  of  individual  polyketide  derivatives  will  be  dealt 
with  in  so  far  as  they  concern  the  main  principles  of  the 
subject. 

When  keten  is  allowed  to  stand  under  pressure  at  ordinary 
temperatures,  it  becomes  converted  into  the  dimolecular  form, 
diketen,  whose  constitution  will  be  discussed  later.  On  treat- 
ment with  pyridine  in  benzene  solution,  this  diketen  (or  keten 
itself)  can  be  transformed  into  dehydracetic  acid. 

There  is  some  dispute  as  to  the  actual  formula  of  the  last 
body,  but  for  the  present  we  may  adopt  one  of  those  proposed, 
and  deal  with  the  whole  question  later. 

CH3.CO.CH2.C          CO 

II  I 

CH       CH2 


Dehydracetic  acid. 

This  substance,  dehydracetic  acid,  is  one  of  the  most 
important  of  the  polyketide  derivatives,  at  least  from  the 
synthetic  point  of  view.  From  it,  by  three  different  reactions, 
we  can  prepare  derivatives  of  the  benzene  series,  the  pyridines 
and  the  pyrones.  The  first  of  these  is  obtained  by  the  action 
of  alkalis  on  dehydracetic  acid,  and  the  reaction  probably  takes 
the  following  course : — 

1  Collie,  Proc.  Cltem.  Soc.,  1907,  23,  230. 


w 

o 
o 

Q 
?i 

W 
o 

—  o 

W 
o 

o* 
o 


o 
o 


1 82      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

In  this  way  both  dihydroxyphenyl-acetic  acid  and  orcinol 
are  formed. 

The  two  other  reactions  mentioned,  resulting  in  pyridine 
and  pyrone  derivatives,  depend  upon  the  intermediate  formation 
of  diacetylacetone  from  dehydracetic  acid  in  the  following 
manner : — 

0 
CH3.CO.CH2.C         CO 


-C02      CHo.CO.CHo.CO 


As  soon  as  the  diacetylacetone  is  formed,  it  may  lose  water  and 
form  dimethyl-pyrone,  thus — 

OH  HO  0 

CH3.C  C.CH3         -H20        CH3.C       C.CH3 

II  II >  II         II 

H.C  C.H  H.C       C.H 


CO 

Diacetylacetone.  Dimethyl  pyrone. 

or  it  may,  in  presence  of  ammonia,  lose  two  molecules  of  water 
and  take  up  instead  the  imino-group  in  the  following  way  : — 


THE   POLYKETIDES   AND    THEIR   DERIVATIVES    183 
NH 

H         H  NH 

OH         HO  /   \ 

/                 \  CH3.C        C.CH3 

CH3.C                       C.CH3  -2H20                ||         || 

II  || >         H.C        C.H 

H.C^                /C.H  V   / 

- CO^  CO 

Diacetylacetone.  Lutidone. 

These  reactions  by  no  means  exhaust  the  possibilities  of 
diacetylacetone,  however,  for  from  it  we  may  produce  benzene, 
naphthalene,  or  isoquinoline  derivatives  by  the  following  steps. 
In  the  first  place,  by  loss  of  one  molecule  of  water,  we  can 
produce  orcinol — 


yH3 

CH3 

O^f 

C 

1 

HfJ 

CH2  -H.,O 

H.(A 

1 

"*T  T 

-•fV 

CO 

jo         ' 

iox 

:o 

1      II 

HO.C^    C.OH 

,/ 

\)H 

\H 

Orcinol 

This  reaction  takes  place  in  strong  alkaline  solutions,  but  if 
we  make  the  alkali  very  dilute  we  can  extract  two  water  mole- 
cules from  diacetylacetone  in  a  different  way,  two  diacetylace- 
tone molecules  being  involved : — 

CH3.  CO  .  CH  :  C .  CH2.  CO  .  CH3 

H2  OH 

H .  C .  CO .  CH2 .  CO .  CH2CO .  CH3 

CH3.C.  CH:C.CH2.CO.CH3 

-2H20  ||  | 

>       H .  C— CO— CH .  CO .  CH2 .  CO .  CH3 

CH 

CHg.C         C.CH2.CO.CH3 

>  II  I 

H.C         C.CO.CH2.CO.CH3 

v 


1 84      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 

This  new  benzenoid  compound  in  turn  is  susceptible  to  the 
action  of  less  dilute  alkalis,  losing  another  molecule  of  water 
and  forming  the  naphthalene  derivative  shown  below — 


CH      CH2 

CH3.CX      C        CO— CH3 

I  II 

H.C  C  CHsr-CO.CH8 

C         CO 

in 


CH      CH2 
-H2o      CH3.C          C         C.CH3 


H.C          C          C .  CO .  CHc 

\  /\    / 
C         CO 

in 


CH3. 
H.C 


CH        CH 
\/    \ 

C  C.CHg 

II       I 

C  C .  CO  .  CH3 

/\    ^ 

C  C 


OH 


O 


H 


THE   POLYKETIDES   AND    THEIR   DERIVATIVES    185 

By  allowing  the  benzene  compound  to  stand  at  ordinary  tem- 
peratures in  presence  of  ammonia,  an  isoquinoline  derivative 
is  obtained — 

CH        CH 

CH3.C  C         C(OH)— CH3 

II  I 

H.C          C 

CX      C(OH) 

I  II 

OH       CH— CO— CH3 


CH       CH 

/  \/   \ 
CH3.C         C          C.CH3 

III 
H.C          C          NH 

\//\/ 

C          C 

I      II 

OH       CH .  CO .  CH3 


CH       CH 

CHg.C  C  C.CHg 

>  II  I  I 

H.C          C          N 

\  </  \  # 
C          C 

OH       CH2COCH3 

We  may  summarize  these  reactions  in  the  following  scheme, 
and  then  proceed  to  the  examination  in  detail  of  the  various 
substances  to  which  we  have  called  attention. 


i86      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

Keten    ---  >      Acetic  acid 

Polymerization 
V 

Acetyl-keten    —  —  >      Acetoacetic  acid 
Triacetic  lactone  !  Polymerization 

*"""""'-  Dehydracetic  acid  —  >    Isomeric  acid 


Heating 

Alkali  Acids         ^     acids 

Orcinol  <-  ^-Orcinol  Pimethyl-pyrone  Lutidone 

JBa(OH)2 
Diacetylacetone 

I  Very  dilute  alkali 
V 
Benzene  derivative 

Dilute  alkali 
4- 

Naphthalene  derivative  Isoquinoline  derivative. 

The  root-substance  of  the  polyketide  class,  keten  itself, 
was  first  prepared  1  by  the  action  of  a  white-hot  platinum  wire 
upon  acetic  anhydride.  About  a  year  later  it  was  shown  '2  that 
it  could  also  be  obtained  by  the  removal  of  the  bromine  from 
bromacetyl-bromide,  a  method  which  has  been  applied  in  the 
case  of  ketene  homologues  also.  Keten  itself  is  a  colourless 
gas  at  ordinary  temperatures,  condenses  in  solid  carbon  dioxide 
to  a  colourless  liquid,  and  rapidly  polymerizes  to  a  brown  oil. 
Both  keten  and  its  polymers  have  a  peculiar  penetrating  odour. 

Keten  may  be  considered  to  be  a  second  anhydride  of  acetic 
acid  ;  for,  just  as  ordinary  acetic  anhydride  is  obtained  by  the 
removal  of  a  molecule  of  water  from  two  molecules  of  acetic 
acid,  keten  is  obtained  by  withdrawing  a  molecule  of  water 
from  a  single  molecule  of  the  acid. 

CH3.CO.OH  CH3.CO\ 

-  H20     =  )0 

CH3.CO.OH  CH3.COX 

H        OH 

|  |  -  H20     =  CH2:CO 

CH2  .  CO 

1  Wilsmore  and  Stewart,  Nature,  1907,  75,  510  ;  Wilsmore,  Trans.  Chem.  Soc., 
1907,  91,  1938. 

2  Staudinger  and  Klever,  Ber.,  1908,  41,  594. 


THE   POLYKETIDES   AND    THEIR   DERIVATIVES    187 

From  this  it  follows  that  keten  should  give  most  of  the  usual 
anhydride  reactions,  and  this  has  been  shown  to  be  the  case. 
When  passed  into  water  it  yields  acetic  acid  \  alcohol  reacts 
with  it  to  form  ethyl  acetate;  aniline  produces  acetanilide; 
and  ammonia  forms  acetamide.  Keten  interacts  with  bromine 
to  form  bromacetylbromide,  with  hydrochloric  acid  to  give 
acetyl  chloride.  Thioacetic  anhydride  is  produced  by  the  action 
of  liquid  sulphuretted  hydrogen  upon  keten.1 

"We  have  already  mentioned  that  if  keten  is  allowed  to 
stand  at  ordinary  temperatures  it  yields  a  brown  condensation 
product.  When  this  is  distilled,  the  dimolecular  polymer  of 
keten  passes  over  as  a  clear  liquid  having  a  very  pungent 
odour.2  This  dimolecular  keten,  like  its  parent  substance,  is  a 
very  reactive  body.  When  added  to  water,  it  slowly  dissolves, 
yielding  a  strongly  acid  solution  which,  on  boiling  (especially 
in  presence  of  hydrochloric  acid),  gives  up  acetone  and  carbon 
dioxide,  losing  its  acid  properties  in  the  process.  When  it  is 
added  to  aniline,  dimolecular  keten  forms  acetoacetic  anilide, 
while  with  phenylhydrazine  it  produces  a  hydrazone-hydrazide. 
These  reactions  are  easily  explained  by  assuming  that  the 
substance  is  acetyl-keten,  for  then  the  three  cases  mentioned 
may  be  expressed  by  the  following  equations : — 

CH3 .  CO  .  CH :  CO  +  H20  =  CH3 .  CO .  CH2 .  COOH 

=  CH3.CO.CH3  +  C02 

CH3 .  CO .  CH :  CO  +  NH2 .  C6H5  =  CH3 .  CO.CH2 .  CO.NH.C6H5 
CH3 . CO . CH : CO  +  2NH2 .  NH .  C6H5 


On  the  other  hand,  Staudinger  3  put  forward  the  view  that 
diketen  was  a  tetramethylene  derivative,  and  Wilsmore,4  after 
a  thorough  examination  of  the  compound's  properties,  inclines 
to  this  view.  He  finds  that  when  diketen,  dissolved  in  carbon 
disulphide  or  carbon  tetrachloride,  is  heated  first  with  bromine 
and  then  with  alcohol,  it  yields  y-bromo-acetoacetic  ester. 
This  tends  to  prove  that  diketen  has  the  structure — 

1  Chick  and  Wilsmore,  Proc.  Chem.  800.,  1908,  24,  78. 

2  Ibid.,  Trans.  Chem.  Soc.,  1908,  93,  946. 

3  Staudinger,  Ber.,  1909,  42,  4908. 

4  Wilsmore,  private  communication  to  the  author. 


iSS      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 


CHo— CO 


CO 

for  on   this   assumption    the 
expressed  simply  thus — 

CH2— CO        Br,        Br.CH< 


— CH2 

series    of 


reactions  would    be 


io- 


-CO     +  Eton     Br .  CH2— CO 


> — CH2  Br.CO — CH2     -  HBr   EtO.CO — CH2 

Diketen.  7-Bromo-acetoacetyl  bromide.  7-Bromo-acetoacetic  ester. 
If  diketen  were  acetyl-keten,  the  product  would  be  the  a-brouio- 
derivative,  not  the  7 -compound.  The  production  of  the  anilide 
and  hydrazone-hydrazide  could  also  be  expressed  in  accordance 
with  this  ring  formula  for  diketen. 

If  we  assume  the  cyclic  structure  for  the  substance,  there 
are  three  possible  formulae  which  must  be  considered — 
CH2— CO  CH=C.OH  CH=C.OH 

CO — CHa  CO  — CH2  HO .  C~  -CH 

(I.)  (II.)  (III.) 

Against  the  second  and  third  of  these  Wilsmore  adduces 
the  fact  that  diketen  may  be  boiled  with  phenylisocyanate 
without  any  interaction  taking  place  between  the  two  com- 
pounds. This  proves  that  the  presence  of  hydroxyl  groups  in 
diketen  is  very  improbable.  The  refractivity  of  the  substance 
does  not  throw  any  very  definite  light  upon  the  constitution. 
Wilsmore l  has  recently  determined  the  refractive  index  of  the 
compound,  and  finds  the  following  : — 


Calculated  for— 
(L)  CHS—  CO                            j 

CO  —  CH.                         1 

18-528 

18-782                 0-472 

(II.)CH=C.OH                      J 
CO-CH.                           1 

19-542 

19-728                 0635 

(in.)  CH=C  .  OH                      j 
HO.C=CH                            ) 

20-556 

20-664                 0-798 

(IV.)  CH,.CO.CH=CO 

20-364 

20489                 0-702 

Observed  for  diketen 

20-017 

20-144                  0-674 

1  Wilsmore,  private  communication  to  the  author. 


THE   POLYKETIDES   AND    THEIR  DERIVATIVES    189 

The  problem  of  the  constitution  of  diketen  must  therefore 
be  regarded  as  still  sub  judice,  but  the  preponderating  evidence 
from  the  chemical  side  points  to  the  compound  being  1,  3- 
diketo- te  tramethy  lene. 

When  reduced,1  diketen  yields  butyraldehyde,  the  reaction 
probably  taking  the  course  shown  below — 

CO — CH2   +2H  HO.CH— CH2_H2o  CH— CH2 

|          | >        |         |     HI         I 

OH2— CO  CH2— CO  CH— CO 


CH2— CO  CH2— CHO 

From  the  monoketide  ethyl  acetate  or  from  diketen  we 
can  obtain  the  diketide  acetoacetic  ester,  whose  properties  are 
so  well  known  that  it  is  unnecessary  to  recapitulate  them  here ; 
we  may  therefore  pass  at  once  to  the  consideration  of  the  next 
polyketide  derivative — dehydracetic  acid. 

This  substance  can  be  obtained  by  polymerizing  keten  or 
diketen  in  benzene  solution  by  means  of  pyridine  or  by  gentle 
heating;  but  it  is  best  prepared  by  the  following  method. 
When  acetoacetic  ester  is  heated  under  a  reflux  condenser  for  a 
time,  it  loses  two  molecules  of  alcohol,  and  is  thus  converted 
into  dehydracetic  acid,  CsHsO*.  This  withdrawal  of  alcohol 
may  be  supposed  to  take  place  in  either  of  two  ways.  In  the 
first  case,  the  two  molecules  react  together  to  form  one  long 
single  chain,  which  then  folds  back  on  itself  and  loses  a  second 
alcohol  molecule,  as  shown  below — 

CH3.CO.CH2.CO  {GET  '&]•  CH3CO.CH3  COOEt  — *•  CH-j.CO.  CHj.CO.CHj-CO.CH^COOEt 


-*^  CH^CO.CH,.^     CO 

CH3.CO.CH,.C         CO 3  ||          I 

I    1  II     I 

H.C        CH,  H.C         CH, 

\6  c6 

Collie's  Formula. 

In  the  second  possible  method  of  formation,  one  acetoacetic 
ester  molecule  reacts  in  the  enolic,  the  other  in  the  ketonic  form — 

1  Wilsmore,  private  communication  to  the  author. 


190      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 


CH.C 


CO 

nl 


CH,.C' 


H.C        IHJCH.CO.CH, 


H.C 


\6 


H.CO.CH3 


Feist's  Formula. 

It  will  be  seen  at  once  that  the  two  methods  do  not  lead  to 
identical  results ;  the  first,  proposed  by  Collie,1  yields  the  lactone 
of  tetracetic  acid  ;  while  the  second,  brought  forward  by  Feist,2 
leads  to  the  same  nucleus,  but  produces  two  side  chains  instead  of 
one.  The  Collie  formula  fails  to  explain  the  presence  of  phenyl- 
methyl-pyrazyl-phenyl-methyl-pyrazolone  as  a  bye-product  in 
the  interaction  of  phenyl-hydrazine  and  dehydracetic  acid ; 3 
while  the  Feist  formula  cannot  be  brought  into  agreement  with  the 
fact  that  with  phosphorus  pentachloride  dehydracetic  acid  reacts 
as  if  it  contained  two  hydroxyl  groups.4  Both  formulae  represent 
the  properties  of  the  compound  almost  equally  well,  and  so  far  it 
has  been  impossible  to  say  which  is  the  correct  one.  In  the  fol- 
lowing pages  the  Collie  formula  will  be  adopted,  as  its  decompo- 
sitions are  more  easily  represented  than  those  of  the  Feist  formula. 

It  will  be  noticed  that  the  polyketide  series  which  we  have 
described  is  not  quite  complete,  as  we  have  omitted  to  deal 
with  triacetic  acid.  This  omission  we  can  now  remedy.  When 
dehydracetic  acid  is  heated  with  ninety  per  cent,  sulphuric  acid 
the  ring  opens,  acetic  acid  is  split  off,  and  the  ring  closes  again, 
forming  triacetic  lactone 5 — 

,\      ?H 

CH3.CO.CH2.C 


CH3.CO.CH2.C       CO 


COOH  CH3.CO.CH2.CO  COOH 


H.O       CH? 

CO 

I 


OH 
CH3.C   COOH 


H.C;     CH 

CO 


IV 

1  Collie,  Trans.  Chem.  Soc.,  1891,  59,  179. 

2  Feist,  Annalen,  1890,  257,  253. 

4  Collie,  Trans.  Chem.  Soc.,  1891,  69,  179. 


H2C        CH2 
CO.OH^H 
III 


3  Benary,  Ber.,  1910,  43,  1070. 
6  Ibid.,  1891,  59,  617. 


THE   POLYKETIDES  AND    THEIR   DERIVATIVES    191 

From  triacetic  lactone  we  can  reproduce  dehydracetic  acid  by 
the  action  of  acetic  anhydride  in  presence  of  sulphuric  acid. 

This  production  of  triacetic  lactone,  however,  is  not  the  only 
reaction  brought  about  by  the  action  of  sulphuric  acid.  If  we 
dilute  the  sulphuric  acid  a  little,  using  eighty-five  per  cent, 
instead  of  ninety  per  cent,  strength,  the  action  takes  quite  a 
different  form.1  As  in  the  previous  case,  water  is  added  on, 
the  ring  opens,  and  tetracetic  acid  is  formed ;  but  instead  of 
breaking  down  into  triacetic  and  acetic  acids,  the  substance 
enolizes  in  a  new  place  and  again  loses  water  to  form  a  new 
acid — 

OH  HO 

I  I 

CH3.CO       CO.CH2.COOH       CH3.C         C.CH2.COOH 

II  II         I! 

CH2     CH2 >          H.C         C.H 

\    /  \    / 

CO  CO 

Tetracetic  acid.  Enolic  form. 

0 

y\ 

CH3.C          C.CH2.COOH 

II  II 

H.C          C.H 

\    / 

CO 

Isomer  of  dehydracetic  acid. 


This  sensitiveness  to  very  slight  variations  in  the  reagents  used 
is  typical  of  the  polyketide  series,  as  has  already  been  pointed 
out  in  the  case  of  the  action  of  weak  and  stronger  alkalis  upon 
diacetylacetone. 

The  action  of  concentrated  hydrochloric  acid,  again,  differs 
from  those  of  the  two  sulphuric  acid  solutions  we  have  just 
described.  Boiling  concentrated  hydrochloric  acid  converts 
dehydracetic  acid  into  dimethyl-pyrone,  the  reaction  probably 
taking  place  in  the  following  way  : — 

1  Collie  and  Hilditch,  Trans.  Chem.  Soc.,  1907,  91,  787. 


192      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 


CH3.CO.CH3.C       CO 


CH3.CO.CH,. 

H-HoO      . 


COOH   CH3.CO.CHa.CO 

-CO2   v_ 


CO 


CH 


OH  HO 
CH3.C        C.CH3 


C.H 


H.C 


CH,    CH, 
CO 


When  the  dimethyl-pyrone  thus  obtained  is  analyzed,  how- 
ever, it  is  found  to  have  the  composition  CvHgC^Cl,  which  cor- 
responds to  a  compound  of  one  molecule  of  dimethyl-pyrone 
with  one  molecule  of  hydrochloric  acid.  The  substance  is  not 
a  chlorine  substituted  pyrone  derivative,  but  behaves  exactly 
like  the  hydrochloride  of  an  organic  base.  Collie  and  Tickle,1 
who  were  the  discoverers  of  this  class  of  substance,  prepared 
a  series  of  compounds  of  dimethyl-pyrone  with  many  of  the 
common  acids,  both  organic  and  inorganic,  as  well  as  metallic 
double  salts,  and  from  a  study  of  their  properties  drew  the  con- 
clusion that  the  oxygen  atom  which  forms  the  bridge  in  the 
pyrone  nucleus  has  basic  properties  akin  to  those  of  a  tertiary 
nitrogen  atom.  Thus,  just  as  tertiary  amines  form  ammonium 
salts,  divalent  oxygen  compounds  may  unite  with  acids  to  form 
"  oxonium  salts."  The  compound  of  dimethyl-pyrone  with 
hydrochloric  acid  would  on  this  hypothesis  be  represented  by 
the  formula — 

H         Cl 

\    / 

O 

CH3.C         C.CH3 

II  II 

H.C          C.H 

V      :  .„•' ,-.., 

1  Collie  and  Tickle,  Trans.  Chem.  Soc.,  1899,  75,  710. 


THE   POLYKETIDES   AND    THEIR   DERIVATIVES    193 

Dimethyl-pyrone  is  a  white  crystalline  solid,  subliming  at 
low  temperatures  and  easily  soluble  in  most  organic  liquids. 
With  acids  it  forms  well- crystallized  salts,  soluble  in,  but 
hydrolyzed  by,  water.  Though  it  contains  a  carbonyl  group,  it 
does  not  react  with  either  hydroxylamine  or  phenylhydrazine. 
This  peculiar  behaviour  has  led  Collie *  to  put  forward  the  view 
that  not  one  but  both  the  oxygen  atoms  in  the  pyrone  nucleus 
are  quadrivalent  in  the  oxonium  salts  ;  while  in  the  base  itself 
one  oxygen  atom  is  supposed  to  be  always  quadrivalent.  On 
this  view  the  formulae  of  dimethyl-pyrone  and  its  hydrochloride 
would  be  written  thus — 

0 

CH3.C         C.CH3  CH3.C  C.CH3 

H.C 

\ 


|  H-0-C1H 
/ 

c 

This  view  of  the  pyrone  structure  is  supported  to  a  certain 
extent  by  an  examination  of  the  refractive  indices  of  pyrone 
derivatives  which  has  been  carried  out  by  Miss  Homfray.2  In 
both  of  the  above  formulae  the  peculiar  resemblance  to  the 
benzenoid  type  is  manifest,  and  Collie  has  been  led  to  suggest 
that  the  root-substance  of  the  pyrone  class  has  a  structure  which 
resembles  that  of  pyridine.  To  this  hypothethical  compound 
he  has  given  the  name  "  oxene"  3  as  the  compound  is  the  oxygen 
analogue  of  benzene  and  pyridine. 

H  H 


C.H  H.C  C.H 


N  O 

S\  S\  S\ 

HC        CH  HC        CH         HC        CH 

I          II  I          II  I          II 

HC        CH  HC        CH         HC        CH 

*/  V 

c  c 


A 


Benzene.  Pyridine.  Oxene. 

1  Collie,  Trans.  Chem.  Soc.,  1904,  85,  971;  cf.  Willstatter  and  Pummerer, 
Ber.,  1904,  3733  ;  1905,  38,  1461. 

2  Homfray,  Trans.  Chem.  Soc.,  1905,  87,  1443. 
1  Collie,  Trans.  Chem.  8oo.t  1904,  85,  971. 

0 


194      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

This  view  lias  certain  advantages,  for  upon  the  ordinary 
formula  it  is  difficult  to  explain  the  comparative  stability  of 
the  pyrone  compounds. 

Before  dealing  with  the  hydration  product  of  dimethyl- 
pyrone,  mention  may  be  made  of  a  substance1  which  stands 
midway  between  the  pyrone  and  benzene  series.  On  treatment 
with  dilute  alkalis,  dimethyl-pyrone  is  converted  into  an  isomeric 
body  which  appears  to  have  the  following  constitution : — 

0 

CH2:C         C.CH3 

I  II 

H.C         C.H 

v 


)H 

When  this  substance  is  boiled  with  acids  it  is  converted 
into  the  corresponding  salt  of  dimethyl-pyrone.  This  change 
involves  only  the  wandering  of  a  hydrogen  atom  from  the 
oxygen  to  the  methylene  group.  On  treatment  with  strong 
alkali  the  substance  undergoes  a  more  complicated  isomeric 
change  and  yields  orcinol.  The  steps  involved  in  this  reaction 
are  probably  the  following  :  — 

0  OH  HO 

CH2:C         C.CH3     +H20    CH2  =  C  C  .  CH3 

I          II  --  >  |  II 

HC        CH  HC  CH 


OH  OH 

CH2HO  CH 

s      \  s  \ 

HO—  C  C—  CH3  _H2o  HO-C          C—  CH3 

I  II  --  >  |  II 

HC  CH  HC          CH 


. 

NX  c 

OH  OH 

1  Collie  and  Stewart,  unpublished  observation. 


THE   POLYKETIDES   AND    THEIR   DERIVATIVES    195 

Collie  1  has  prepared  the  corresponding  diacetyl  derivative, 
which  behaves  in  a  similar  manner ;  with  acids  it  is  converted 
into  the  salt  of  diacetyl-dimethyl-pyrone,  while  alkalis  change 
it  to  diacetyl-orcinol. 

We  must  now  turn  to  the  substance  which  is  obtained  by 
the  addition  of  one  molecule  of  water  to  dimethyl-pyrone.  The 
action  requires  the  presence  of  alkalis,  and  is  best  carried  out 
by  boiling  dimethyl-pyrone  with  a  strong  solution  of  barium 
hydrate.  After  neutralizing  the  excess  of  alkali,  the  solution  is 
shaken  out  with  ether,  by  which  means  diacetyl-acetone  is 
extracted.  The  course  of  the  reaction  involves  the  formation 
and  decomposition  of  the  barium  salt  of  diacetyl-acetone — 

0  0— Ba— 0 

CH3.C        C.CH3  CHg.C  C.CHg 

II          II >  II  II 

H.C        C.H  H.C  C.H 

v       >  v 

OH    HO     ^ 

CHg.C  C.CHg  CHg.CO  CO.CHg 

II      II       — >       I       I 

H.C         C.H  CH2     CH2 

\  /  \    / 

CO  CO 

Diacetyl-acetone  forms  colourless  mica-like  crystals,  which 
volatilize  at  ordinary  temperatures.  It  is  unstable,  losing 
water  with  great  ease,  and  changing  into  dimethyl-pyrone; 
while,  under  certain  conditions,  it  breaks  down  into  acetone 
and  acetic  acid.  It  forms  one  of  the  very  small  class  of  tri- 
ketones,  and  with  it  we  reach  the  highest  stable  member  of  the 
polyketide  class. 

At  the  beginning  of  this  chapter  we  called  attention  to  the 
view  that  many  of  the  simple  substances  found  in  plants  were 
not  the  results  of  direct  synthesis,  but  rather  of  synthesis 
followed  by  decomposition,  and  in  diacetylacetone  we  have  a 
substance  which  will  serve  as  a  typical  example  of  this  method. 
In  the  first  place,  by  spontaneous  dehydration  at  ordinary 

1  Collie,  Trans.  Chem.  800.,  1904,  85,  971. 


196      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

temperatures,  we  get  dimethyl-pyrone.     By  using  acid  dehy- 
drating agents  we  can  form  orcinol l  — 

CH3  CH 

/  /    \ 

CO      0  =  0— CH3  CO        C— CH3 

I  I  >     \  I 

CH2  CH2  CH2       CH2 

XCOX  CO 


-CH3 


Stronger  dehydrating  agents  produce  scarlet  dye-stuffs,2  which 
are  probably  similar  to  those  obtained  by  dehydrating  di- 
methyl-pyrone. We  have  already  described  the  formation  of 
the  pyridine,  benzene,  naphthalene,  and  isoquinoline  deriva- 
tives — 

NH 

CH3.C          C.CH3  CH3/XCH2COCH3 

II  II 

H.O          O.H  HJCO.CH2COCH3 

CO  OH 

Pyridine  compound.  Benzene  compound. 

H        H 
C         C 


CH3.C        C        C.CH3 

II          I          I 
H  .  C        C        C  .  CO  .  CH3 

\/-w 

C         C 

OH      OH  OH    CH2.COCH3 

Naphthalene  compound.  Isoquinoline  compound. 

1  Collie  and  Myers,  Trans.  Chem.  8oc.,  1893,  63,  122. 

2  Collie  and  Stewart,  unpublished  observation. 


THE   POLYKETIDES  AND    THEIR  DERIVATIVES    197 

There  is  one  polyketide  derivative  which  we  have  not  yet 
mentioned.  If  we  treat  keten  with  hydrochloric  acid  and  with 
ethyl  alcohol  we  get  acetyl  chloride  and  ethyl  acetate ;  from  the 
latter  we  can  produce  acetoacetic  ester,  and  thence  by  the  aid 
of  the  acetyl  chloride  we  can  synthesize  acetylacetone.  This 
substance  completes  the  series  of  ketones  which  we  have  derived 
from  the  simple  keten  group,  and  it  may  be  well  to  give  a  table 
showing  the  relations  of  each  member  to  the  others. 


Ketens. 

Acids. 

Ketonee. 

Keten 

(CH2  :  CO) 

Diketen 
(CH2  :  C0)2 

Acetic 
H.(CH2.CO).OH 

Acetoacetic 
H  .  (CH2  .  CO)2OH 

Acetone 
H.(CH2.CO).CH3 

Acetylacetone 
H  .  (CH2  .  C0)2  .  CH3 

Triacetic 
H.(CH2.CO)3OH 

Tetracetic 
H.(CH2.COXOH 


Diacetylacetone 
H.(CH2.CO)3.CH3 


We  may  subjoin  another  tabular  statement  (see  next  page), 
which  brings  out  the  relations  between  dehydracetic  acid,  the 
pyrones,  and  the  aromatic  series. 

So  far,  we  have  described  only  those  polyketide  derivatives 
which  can  be  obtained  from  keten  by  methods  which  have 
actually  been  worked  out  experimentally.  There  is  one  most 
important  class  of  substances,  however,  which  do  not  come 
within  this  category,  though,  theoretically,  they  belong  to  the 
polyketide  derivatives.  The  sugars — though  we  at  present 
have  no  means  of  synthesizing  them  from  keten,  or  any  of  its 
simple  derivatives — are  very  closely  related  to  the  keten  group. 
Collie 1  has  indicated  the  lines  which  should  be  followed  in  such 
syntheses ;  but  at  present  the  proper  conditions  have  not  been 
discovered. 

Wills  tatter  and  Pummerer 2  have  shown  that  when  we  act 
upon  pyrone  with  metallic  alcoholates  bishydroxymethylene- 
acetone  derivatives  are  produced.  If  we  consider  the  effect  of 
opening  the  pyrone  ring  with  a  water-molecule  instead  of  a 


1  Collie,  Trans.  Chem.  8oo.t  1907,  91,  1806. 

2  Willstatter  and  Pummerer,  Ber.,  1905,  38, 1461. 


198      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 


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THE   POLYKETIDES  AND    THEIR  DERIVATIVES      199 

molecule  of  alcoholate,  we  find  that  bishydroxyinethylene- 
acetone  itself  (2)  would  result.  If  this  could  be  converted 
into  the  isomeric  form  (3)  by  the  wandering  of  a  hydrogen 
atom,  and  the  resulting  compound  could  be  induced  to  combine 
with  two  molecules  of  water  at  the  double  bonds,  the  pentose 
(4)  would  be  produced.  So  far,  no  successful  attempt  has 
been  made  to  produce  this  change,  but  if  the  proper  conditions 
could  be  found  there  seems  no  reason  why  it  should  not  be 
carried  out. 


0 
H.C        C.H  HO. C.H    H.C.OH 


'V 


H.C        C.H  H.C  C.H 

\co/X 


V  x 

(1.) 

HO .  C .  H        ti^  HO  .  CH2 

II  I 

C.H  HO. C.H 


C.OH  H.C.OH 

C.H  HO . C . H 

I  I 

CO  CO 

i  .    1 

(3.)  (4.) 

By  successive  hydration  and  dehydration  a  different  type  of 
product  would  result — 


CO 

CO 

Ao 

,      io 

iSb 

CH2 

C.H 

HO.  C.H 

•  i° 

HO.C 

HO.  C.OH 

<!o 

io 

C.OH 

1 
H  .  C  .  OH 

H.C 

H.C.H 

1 

CH2 

CH2 

CH2 

CH2 

CH2 

CH2 

CH2 

i 

i 

i 

i 

i 

1 

1 

1 

1 

i 

(I-) 

(II.) 

(III.) 

(IV.) 

(V.) 

(VI.) 

200      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

If  we  take  as  our  starting-point  the  group  (I.)  and  convert 
it  into  the  enolic  form  (II.),  we  can  then  add  a  molecule  of 
water  on  to  the  double  bond  to  form  (III.)  This  substance 
could  then  be  dehydrated  to  produce  (IV.),  to  which  water 
might  be  again  attached,  giving  (V.),  in  which  two  hydroxyl 
groups  are  attached  to  the  same  carbon  atom.  This  compound 
would  lose  a  molecule  of  water,  leaving  (VI.). 

A  comparison  of  the  formulae  (I.)  and  (VI.)  shows  that  the 
whole  process  implies  a  wandering  of  the  hydrogen  atoms  to 
the  lower  end  of  the  chain,  and  a  corresponding  migration  of 
the  oxygen  atoms  to  the  other.  This  purely  theoretical  series 
of  actions  could  then  be  repeated,  and  the  final  result  would  be 
a  loss  of  carbon  dioxide  from  one  end  of  the  chain,  and  a 
building  up  of  an  aliphatic  chain  at  the  other  end.  Some 
such  process  may  take  place  in  the  living  organism  during  the 
formation  of  oils  or  fats,  and  the  liberation  of  carbon  dioxide  in 
respiration  would  be  explicable  in  the  same  way. 

We  have  now  completed  our  survey  of  the  polyketides  and 
their  derivatives,  and  in  conclusion  we  may  point  out  the 
salient  features  of  the  classes  with  which  we  have  dealt.  The 
polyketens  themselves,  (CH2 :  C0)n,  are  remarkable  chiefly  for 
their  great  reactivity ;  they  are  easily  attacked  by  any  ordinary 
reagents,  and  further  possess  the  power  of  polymerization  to  a 
marked  degree.  Their  union  with  acid  or  neutral  substances 
produces  compounds  which  in  turn  are  reactive,  though  not  to 
the  same  extent  as  the  parent  bodies ;  but  if,  on  the  other 
hand,  the  polyketens  be  combined  with  basic  substances,  the 
products  are  not  at  all  reactive.  The  higher  members  of  the 
polyketide  group  when  combined  with  water  tend  spontaneously 
to  lose  carbon  dioxide,  and  become  converted  into  ketonic  com- 
pounds of  a  lower  series,  which  in  turn  may  be  dehydrated 
to  form  benzenoid  or  pyrone  derivatives,  both  of  which  are 
comparatively  stable.  Thus  these  substances  as  a  class  illus- 
trate the  dual  tendencies  at  work  in  the  whole  field  of  organic 
chemistry — the  synthetic  and  the  analytic ;  the  simpler,  more 
reactive  group  tending  always  to  attract  other  atoms  and  form 
more  complex  derivatives,  while  these  in  turn  become  unstable 
and  break  down  into  new  and  more  stable  forms. 


CHAPTEK  IX 

THE  QUINOLES 

1.  Introductory. 

IF  in  the  formula  of  benzoquinone  (I.)  we  replace  one  of  the 
carbonyl  radicles  by  a  secondary  (II.)  or  a  tertiary  (III.) 
alcohol  radicle,  we  shall  obtain  the  structural  formulae  of  two 
new  types  of  compounds  which  have  been  termed  quinoles  by 
Bamberger.1  Compounds  of  the  type  (II.)  are  secondary 
quinoles  ;  those  of  the  structure  (III.)  are  tertiary  compounds. 

0  H        OH  R        OH 

II  \  /  \  / 

c  c  c 

H.C        C.H  H.C        C.H  H.C        C.H 

II         II  II          II  II          II 

H.C        C.H  H.C        C.H  H.C        C.H 

\y  \/ 

c  c 

II  II  II 

000 

(I.)  (II.)  (III.) 

An  examination  of  the  second  formula  will  show  that  it  is  the 
mono-ketonic  form  of  ordinary  hydroquinone. 

Derivatives  of  these  substances  had  long  been  known  in 
the  anthracene  series,  oxanthranol  being  the  simplest  of  them  : 

H        OH 
CH        C        CH 
H/VVX 

i      ii      ii     i 

HC         C          C        CH 

/\/\^ 
H         C        CH 

o  -          - 

Oxanthranol 
1  Bamberger,  Ber.,  1900,  33,  3607. 


202      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

but  it  was  not  until  1895  that  mono-nuclear  quinoles  were 
discovered  by  Zincke,1  and  with  this  research  the  history  of 
the  quinoles  proper  begins;  for  in  the  anthracene  derivatives 
the  specific  character  of  the  quinole  nucleus  is  to  a  great 
extent  concealed  owing  to  the  complications  introduced  into 
the  molecule  by  the  presence  of  the  two  benzene  nuclei. 

For  many  years  Zincke  had  been  engaged  upon  the  study  of 
the  action  of  chlorine  upon  various  aromatic  substances;  and 
his  results  showed  that  this  reagent  was  capable  of  converting 
the  stable  and  comparatively  inert  benzenoid  nucleus  into  a 
most  varied  and  reactive  series  of  products.  One  example  will 
suffice :  the  action  of  chlorine  upon  catechol.2  The  action 
takes  place  in  the  following  stages.  The  first  product  is 
tetrachloro-o-quinone  (II.),  which  is  then  further  acted  upon 
by  chlorine  to  give  hexachloro-0-diketo-K-hexen  (III.).  When 
this  substance  is  heated  with  water,  it  undergoes  intramolecular 
change,  the  six-membered  ring  being  converted  into  a  five- 
membered  one,  and  hexachloro-K-penten-hydroxy-carboxylic 
acid  (IV.)  is  produced.  Oxidation  with  chromic  acid  breaks  off 
the  side-chains  and  the  ketone  hexachloro-E-penten  (V.)  results, 
which  on  treatment  with  caustic  soda  opens  up,  yielding 
perchloro- vinyl-aery  lie  acid  (VI.),  from  which  ethylidene- 
propionic  acid  (VII.)  may  be  obtained  by  reduction. 


Cl  01 

A      A 

OH  01.  C        CO  Cl.C        CO 

Cl.C        CO  C]2C        CO 

0  C 

I  /\ 

Cl  Cl      Cl 

(I.)  (II.)  (III.) 

1  Zincke,  Ber.,  1895,  28,  3121. 

2  Zincke,  Ber.,  1888,21,  2719;  1889,22,486;  1891,24,908;  1893,26,2104 
1894,  27,  3364. 


THE   QUINOLES  203 

Cl 

C 

COOH 

GIG 


I 

C 


C1 

OH 


Cl       Cl 
(IV.) 

Cl 
C 
Cl .  C      COOH 

Cl.C 

C.C12 
(VI.)  (VII.) 

When  Zincke  applied  this  reaction  to  para-cresol1  he  found 
that  the  substance  was  unexpectedly  stable,  for  the  end- 
product  of  the  chlorination  process  still  contained  two  nuclear 
hydrogen  atoms  unreplaced  by  chlorine,  CH3 .  CeH2 .  C130.  Ee- 
placing  para-cresol  by  para-toluidine,  he  obtained  as  the  end- 
product  of  the  reaction  the  substance  CH3 .  CeH2 .  C170.  Zincke 
formulates  the  reaction  in  the  following  manner : — 

CH3  CH3  CH3 

I  I  I 

C 

H.C       C.H 

I        II 
H.C       C.H 

v 


(I.) 


C 

C 

#  \ 

S\ 

H.C       C.H 

H.C       C. 

H 

1        II 
Cl  .  C       C  .  Cl 

C12C       C. 
\      / 

Cl 

C 

\  / 

C 

NH2 

II 

NH 

(II.) 

(III.) 

Bamberger,  Ber.,  1900,  33,  3607 

204      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

Cl         CH3  Cl         CH3 

\X  \/ 

c  c 

C1H.C        C.HC1  C1H.C        C.HC1 

II  II 

Cla.C         C.Cla  Cla.C         C.C12 

v  v 

ii  ii 

NH  0 

(IV.)  (V.) 


The  difference  between  the  reactions  of  the  phenol  and  amido- 
compound  is  to  be  ascribed  to  the  fact  that  the  intermediate 
imide  formed  from  the  toludine  is  more  reactive  than  the 
corresponding  keto-chloride  which  is  produced  from  the  cresol. 
Now  if  we  reduce  the  keto-chloride  (V.)  we  obtain  tetra- 
chloro-para-cresol : 


CH 


Cl .  C        C .  Cl 

I      II 

Cl.C        C.C1 

V 

OH 


When  this  was  treated  with  nitric  acid,  Zincke  expected,  by 
analogy  with  the  results  obtained  by  him  in  other  cases,  that  an 
ortho-quinone  of  the  formula  CH3 .  C6C1302  would  be  produced ; 
but  instead  of  this  substance  he  obtained  a  compound  having 
the  formula  CH8 .  C6HC1302.  On  reduction,  this  new  substance 
regenerated  tetrachloro-para-cresol,  and  on  the  grounds  which 
we  shall  deal  with  in  a  later  section,  Zincke  ascribed  to  it  the 
formula — 


THE   QUINOLES  205 

HO        CH3 

X 

Cl .  C        C  .  01 

II       II 

01 . 0        0 .  01 

V 

II 
o 

It  belongs  to  the  quinole  series,  and  in  this  way  a  new  line 
of  research  was  opened  up. 


2.  Methods  of  Preparing  Quinoles. 

The  quinoles  which  have  been  prepared  up  to  the  present 
may  be  divided  into  three  classes :  those  with  no  substituents 
attached  to  the  nucleus ;  quinoles  whose  nuclear  hydrogen  atoms 
have  been  replaced  by  alkyl  radicles ;  and,  finally,  halogen- 
substituted  quinoles.  Since  in  some  instances  it  is  impossible 
to  prepare  the  parent  substances  by  reactions  which  answer 
quite  well  in  the  case  of  derivatives,  it  will  be  most  convenient 
to  classify  the  methods  of  preparation  of  these  substances 
according  to  the  end-products  of  the  reaction ;  and  we  shall 
therefore  take  up  in  turn  the  three  types  of  quinoles. 

I.  Simple  Quinoles. — These  were  obtained  by  Bamberger  x 
in  the  following  manner.  If  we  subject  a  para-alkylated  aryl- 
hydroxylamine  derivative  to  the  action  of  dilute  sulphuric  acid 
or  alum  solution,  the  first  product  at  ordinary  temperatures  is 
an  imido-quinole ;  but  should  the  reaction  be  prolonged,  this 
substance  breaks  down  into  ammonia  and  the  corresponding 
quinole.  If  the  action  be  not  brought  to  an  end  at  this  point, 
intramolecular  change  occurs  and  an  alkyl-substituted  hydro- 
quinone  is  formed.  For  instance,  in  the  case  of  para-tolyl- 
hydroxylamine  the  reaction  takes  place  in  the  stages  illustrated 
by  the  formulae  below. 

1  Bamberger,  JBer.,  1900,  33,  3615. 


206      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 


CH3  HO       CH3       HO       CH3  OH 

v     v      i 


HC   CH    HC   CH    HC   CH    HC   C  CH, 

I    II   ->   II    II  -»   II    I  .  •*   I    I 
HC   CH    HC   CH    HC   CH    HC   CH 

V       V       V      V 

I  II  II  I 

NH.OH  NH  O  OH 

II.  Alkyl-sulstituted  Quinoles. — There  are  three  methods  of 
preparing  this  set  of  derivatives.  In  the  first  place,  we  may 
apply  the  aryl-hydroxylamine  reaction  described  above,  starting 
in  this  case  with  a  di-substituted  aryl-hydroxylamine  instead 
of  a  mono-substituted  one.  For  instance,  in  the  case  of  2,  4- 
dimethyl-phenylhydroxylamine l  we  have  the  following  series 
of  changes,  resulting  in  the  production  of  dimethyl-quinole  :— 

HO         CH3 

v 

XCH 


C.CH3  HC        C.CH3 

v 

NH.OH  NH  0 

Caro's  reagent  applied  to  di-substituted  phenols2  produces  a 
certain  amount  of  the  corresponding  quinole;  but  the  yields 
are  small.  Of  course  in  both  the  aryl-hydroxylamine  and  the 
phenol  which  are  used  as  starting-points  for  the  foregoing  re- 
actions one  of  the  substituent  alkyl  radicles  must  be  in  the 
para-position  to  the  hydroxylamine  residue  or  to  the  hydroxyl 
group. 

A  third  method3  of  preparing  alkyl-substituted   quinoles 
consists  in  the  application  of  Grignard's  reagent  to  substituted 

1  Bamberger,  Ber.,  1900,  33,  3647. 

2  Ibid.,  1903,  36,  2028. 

3  Bamberger  and  Blangey,  Ber.,  1903,  36,  1626. 


THE   QUINOLES  207 

quinones.  Benzoquinone  itself  does  not  give  a  quinole  in  this 
way,  but  when  toluquinone  is  treated  with  magnesium  methyl 
iodide,  a  dimethyl-quinole  is  produced : — 

0  HO        CH3 

II  \'/ 

c  c 

HO        CH  HO        CH 


HO        C.H3  HC        C.CH3 

v       -•     v 

II  II 

O  0 

III.  Halogen-substituted  Quinoles.  —  In  the  introductory 
section  of  this  chapter  we  have  seen  that  these  bodies  may  be 
prepared  by  the  chlorination  of  para-substituted  aromatic 
amines.  The  researches  of  Zincke1  and  of  Auwers2  have 
shown  that  when  halogen-substituted  phenols  are  heated  with 
concentrated  nitric  acid,  the  corresponding  quinoles  are  pro- 
duced. In  this  case  the  intermediate  products  are  cyclic  nitro- 
ketones,  so  that  the  reaction  takes  the  following  course  :  — 


CH3 
C 
Br.C         C.Br 

N02        CH3 

\/ 
C 

Br.C         C.Br 

HO        CH3 

»•;   )< 

Br.C        C.Br 

-->        II          II 
Br.C         C.Br 

v 

ii 

0 

Br.C         C.Br 

v 

in 

Br.C        C.Br 

Y 

II 
0 

Similar  results  are  obtained  when  halogen-substituted  phenols 
are  dissolved  in  glacial  acetic  acid  and  then  treated  with  nitrous 
fumes. 

When  bromine  is  allowed  to  act  upon  para-cresol,  Zincke 
and  Wiederhold  3  found  that  there  are  three  possible  types  of 

1  Zincke,  Ber.,  1895,  28,  3121  ;  1901,  34,  253,  J.  pr.  Ch.,  [2]  1897,  56,  157. 

2  Auwers,  Per.,  1897,  30,  755;  Annalen,  1898,  302,  153. 

3  Zincke  and  Wiederhold,  Annalen,  1901,  320,  199. 


208      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 

reaction  product,  one  or  another  preponderating  according  to 
the  conditions  of  the  experiment.  If  the  bromine  acts  upon 
the  phenol  in  chloroform  solution  at  ordinary  temperatures, 
we  obtain  simply  the  mono-,  di-,  and  tribromo-derivatives  of 
paracresol : — 


C] 

I 

*3 

CH3 

1 

c^ 

C 

HC 

^ 
C.Br 

Br.c" 

C.Br 

II 
r-C 

C.Br2 

II 
Br.C 

C  .  Br, 

When  water  is  substituted  for  chloroform,  we  get  normal  keto- 
bromides,  such  as : — 

CH3 

C 

/  \ 
HC        CH 

II          I 
Br.C         C.Br2 

CO  CO  CO 

But  if  we  allow  bromine  in  excess  to  act  directly  upon  the 
phenol,  without  any  solvent,  in  a  sealed  tube  at  100°  C.  for 
several  hours,  bromine  enters  the  side-chain,  and  we  get  tetra- 
bromo-^-cresol-pseudobromide : — 

H        CH2Br 

v 

Br .  C        C  .  Br 

II          II 
Br .  C         C  .  Br 

;       V 

When  this  substance  is  boiled  with  nitric  acid  (sp.  gr.  1*4)  it 
yields  pentabromo-toluquinole,  which  has  the  following  con- 
stitution : 


THE   QUINOLES  209 


HO         CH2Br 

Y 

Br.C 

ii 

xc 

II 

.Br 

II 
Br.C 

II 
C 

.Br 

3.  The  Properties  of  the  Quinoles. 

As  a  class,  the  quinoles  are  distinguished  by  extreme  re- 
activity and  lability  of  structure.  They  react  with  many  of 
the  ordinary  reagents  with  great  ease ;  and  in  addition  they 
are  capable  of  undergoing  very  far-reaching  isomeric  changes. 
With  the  latter  division  of  their  properties  we  shall  deal  in  a 
special  section;  at  present  we  shall  confine  ourselves  to  the 
action  of  the  commoner  chemical  reagents  upon  compounds  of 
the  quinole  type. 

In  their  general  chemical  character,  the  quinoles  resemble 
weak  acids.  They  are  soluble  in  caustic  alkali,  but  not  to  any 
great  extent  in  sodium  carbonate  solution.  From  this  beha- 
viour we  may  deduce  the  presence  of  a  hydroxyl  group  in  their 
structure. 

When  reducing  agents  such  as  sulphurous  acid,  zinc  dust 
and  acetic  acid,  or  zinc  and  aqueous  ammonium  chloride  are 
employed  upon  quinoles,  reduction  takes  place  with  great  ease. 
Bamberger 1  has  found  that  even  ferrous  sulphate  and  sodium 
carbonate  solution  are  sufficient  to  reduce  a  dimethyl-quinole 
to  the  corresponding  phenol.  This  formation  of  the  benzenoid 
nucleus  in  preference  to  the  quinonoid  one  is,  as  we  shall  see 
later,  one  of  the  most  characteristic  features  of  the  intramole- 
cular changes  which  have  been  observed  in  the  quinole  group. 
The  tendency  is  so  strong  that  reduction  is  brought  about  by 
such  unlikely  substances  as  hydrobromic  acid  and  phosphorus 
pentabromide.2  In  all  these  cases  we  may  formulate  the  reduc- 
tion process  as  a  true  reduction  in  one  of  its  stages,  the  next 
stage  being  the  loss  of  water  or  hydrobromic  acid.  In  the 

1  Bamberger,  Ber.,  1900,  33,  3616. 
8  Auwers,  Ber.,  1902,  35,  445. 


210      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

reduction  by  means  of  pentabromide  of  phosphorus,  the  first 
step  appears  to  be  the  replacement  of  the  hydroxyl  group  of 
the  quinole  by  a  bromine  atom ;  the  hydrobromic  acid  thus 
liberated  then  reacts  as  usual  with  the  quinole.  The  following 
formulae  give  some  idea  of  the  reduction  of  methyl  quinole  by 
zinc  dust,  hydrobromic  acid,  and  phosphorus  pentabromide. 

Zinc  dust  and  acetic  acid— 


HO        CH3                      HO        CH3 

CH3 

X        X 

C 

HC        CH          H2          HC        CH        -H2o 

HC        CH 

II         II            >           II         II            > 

1          II 

HC        CH                       HC        CH 

HC        CH 

V/                                \/ 

\  / 

C                                      C 

C 

i 

0                                HO        H 

1 
OH 

Hydrobromic  acid— 

HO         CH3            Br        CH3                   CH3 

\y         \/           i 

C                            C                            C 

/\           /\           ^\ 

HC         CH            HC         CH            HC         CH 

II          II      >      II          II       >      1          II      • 

•j-  Br2  +  H20 

HC        CH            HC        CH            HC        CH 

\      /                     \      /                    <^.      / 

V         V         V 

II                                    /   \                                     1 

/  \ 

0                     HO         Br                      OH 

Phosphorus  pentabromide  — 

HO         CH3          Br        CH3          Br        CH3 

CH3 

\/                   \/                  \/ 

C                         C                         C 

i 

HC        CH         HC        CH        HC        CH 

/\ 

HC        CH 

II         II      ->       II          II      ->      II          II        -> 

1          II 

HC        CH          HC        CH        HC        CH 

HC         CH 

V       V       V     : 

\  / 

C 

II               II            /  \ 

0                          0                    H        OH 

H 

THE   QUINOLES  211 

From  their  behaviour  towards  alkalis,  it  was  to  be  expected 
that  the  quinoles  would  yield  acyl  derivatives ;  and  this  has 
proved  to  be  actually  the  case.  Mono-acetates  are  produced 
when  quinoles  are  treated  with  acetic  anhydride  or  acetyl 
chloride ;  and  the  benzoyl  derivatives  are  formed  in  the  usual 
way  by  the  Baumann-Schotten  reaction.  It  has  been  found 
that  in  the  case  of  the  quinoles  derived  from  brominated 
phenols,  the  acyl  derivatives  are  even  more  easily  reduced 
than  the  parent  quinoles  are.  Auwers l  mentions  as  an  example 
of  this  the  case  of  tribromo-m-xyloquinole.  This  substance  is 
not  attacked  at  ordinary  temperatures  by  hydrobromic  acid  in 
acetic  acid  solution ;  reduction  begins  only  at  100°  C.  But 
when  the  acetyl  derivative  of  the  quinole  is  subjected  to  the 
same  agent,  it  is  reduced  even  at  ordinary  temperatures  to 
tribromo-xylenol. 

CH3CO.O        CH3  CH3 

\/  I 

C  C 

/\  ^\ 

Br.C        C.Br  Br.C        C.Br 

II          II  >          I          II 

Br.C         C.CH3  Br.C         C.CH3 

v 

i 

OH 


4 


It  is  easy  to  see  that  this  power  of  reduction  which  hydro- 
bromic acid  possesses  must  exert  considerable  influence  in  the 
case  of  the  action  of  acetyl  bromide  upon  quinoles.  While 
acetyl  chloride  yields  the  ordinary  mono-acetate  of  the  quinole 
employed,  it  is  frequently  found  that  acetyl  bromide  produces 
the  acetate  of  the  corresponding  phenol ;  so  that  in  the  latter 
case  the  simple  acetylation  has  been  complicated  by  the 
reduction  of  the  quinole  to  the  phenol  by  means  of  the 
hydrobromic  acid  liberated  in  the  course  of  the  reaction. 
The  reducing  action  of  the  hydrochloric  acid  which  is  liberated 
when  acetyl  chloride  is  used  is  very  much  feebler  than  that  of 
the  hydrobromic  acid ;  and  consequently  the  quinole  acetate  in 
that  case  is  not  transformed  into  the  phenolic  derivative, 

1  Auwers,  Ber.,  1902,  35,  446. 


212      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 


Turning  now  to  the  reagents  which  react  with  carbonyl 
groups,  we  find  that  a  difference  is  to  be  noted  between  two 
classes  of  the  quinoles.  Those  quinoles  which  have  substituents 
in  the  two  positions  ortho  to  the  carbonyl  radicle  follow  the 
usual  rule  in  such  cases  and  do  not  interact  with  phenylhydra- 
zine,  hydroxylamine,  or  semicarbazide.1  The  case  of  an  unsub- 
stituted  quinole  differs  from  this.  Bamberger  and  Eudolf2 
have  found  that  when  xyloquinole  is  treated  with  hydroxyl- 
amine, it  reacts  with  two  molecules  of  the  latter,  giving  a 
substance  which  is  both  an  oxime  and  a  substituted  hydroxyl- 
amine. 

HO         CH3 

v 


H. 


CH .  NH .  OH 


.  C        CH2 

\/ 

C 

II 
N.OH 

With  nitro-phenylhydrazine  and  with  semicarbazide,  the 
same  quinole  gives  cyclic  substances3  having  the  following 
formulae : — 


N02.C6H4.N 


-C 
\ 


NH2CO .  N- 


CH 


HC          C.CH3 
\/ 


HC          C .  CH3 


N: 


From  the  foregoing,  the  salient  features  of  the  quinoles  can 
be  inferred,  and  in  the  following  section  we  shall  show  how 
the  constitution  of  these  substances  may  be  deduced. 

1  Auwers,  Ber.,  1902,  35,  444. 

2  Bamberger  and  Budolf,  Ber.,  1907,  40,  2236. 
•  Bamberger,  Ber.,  1900,  33,  3620. 


THE    QUINOLES  213 


4.  The  Constitution  of  the  Quinoles. 

In  the  previous  section  we  have  dealt  with  most  of  the 
material  which  will  be  required  to  establish  the  structure  of 
the  quinoles ;  and  in  the  present  section  it  will  be  convenient 
to  deal  with  the  question  point  by  point. 

I.  The  quinoles  contain  a  ring  of  six  carbon  atoms.     This 
is  shown    by   their  conversion   into   benzene   derivatives  on 
reduction. 

II.  The  quinoles  contain  a  hydroxyl  group.     This  is  proved 
by  their  yielding  acetyl  derivatives ;  and  also  by  the  fact  that 
they  dissolve  in  alkalis  more  readily  than  in  water,  and  that 
acids  precipitate  them  from  these  alkaline  solutions. 

III.  They  contain  a  carlonyl  group.    The  action  of  phenyl- 
hydrazine,    hydroxylamine,  and    semicarbazide   upon   quinole 
derivatives  establishes  this. 

IV.  Quinoles  have  a  methyl  radicle  in  the  1,  ^-position  to  the 
carlonyl  group.     The  most  convincing  proof  of  this  is  an  indirect 
one.     It  was  found  by  Brady 1  that  quinoles  are  produced  only 
from  phenyl-hydroxylamine  derivatives  which  have  an  alkyl 
group  in  the  para-position  to  the  hydroxylamine  residue.     For 
example,  the  five  compounds  below  gave  no  quinoles  when 
treated  in   the   usual   manner  with   sulphuric   acid  or   alum 
solution : — 


GIL 


NH.OH        NH.OH        NH.OH 
CH3 


'CH3 
NH.OH        NH.OH 

1  See  Bamberger,  Per.,  1900,  33,  3616. 


214      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

but  all  the  following  four  compounds  yielded  quinoles  : — 
CH3  CH3  CH3  CH3 


NH.OH  NH.OH  NH.OH  NH.OH 

It  is  clear  that  quinole  formation  takes  place  only  when  there 
is  a  methyl  group  para  to  the  hydroxylamine  residue ;  and 
since  the  group  — NH.OH  in  the  aryl-hydroxylamines  cor- 
responds to  the  carbonyl  radicle  in  the  quinoles,  we  may  con- 
clude that  in  the  latter  compounds  the  carbonyl  and  methyl 
radicles  are  in  the  para-position  to  one  another. 

Having  advanced  to  this  point,  it  is  clear  that  there  are 
only  three  possible  formulae  for  methyl-quinole  : — 
HO        CH3  H          CH3  H          CH3 

X       /        v 

HC          CH  HC          C.OH  HC          CH 


HC          CH  HC          CH  HC          C.OH 


v 


o  o  o 

(I.)  (II.)  (III.) 

The  third  of  these  is  the  enolic  form  of  an  ortho-diketone  : 

H          CH3 

X 

HC          CH2 

II  I 

HC          CO 

v 

and  since  the  properties  of  methyl-quinole  do  not  correspond 
to  those  which  we  should  expect  to  find  in  ortho-diketones, 
we  may  dismiss  this  formula.  If  we  examine  the  second 
formula,  we  find  that  it  is  a  tautomeric  form  of  cresorcinol ;  so 


THE    QUINOLES  215 

we  may  reject  this  formula  also.     This  leaves  us  with  the  first 
formula  as  the  only  probable  one. 

Further  evidence  in  favour  of  this  structure  is  furnished 
by  the  formation  of  quinoles  from  quinones  by  means  of  the 
Grignard  reaction : — 

CH3     OMgl  CH3    OH 

X  "    v 

CH3.C        C.H   cH3Mgi  CH3.C        C.H  CH3.C        CH 

II          II >          II         II >  ||         || 

H.C        C.H  H.C        C.H  H.C        CH 

v         v        y 

The  yields  are  so  small  that  this  reaction  would  not  in  itself 
furnish  a  perfectly  satisfactory  proof  of  the  quinole  structure  ; 
but  it  lends  additional  weight  to  the  other  proofs. 


5.  Intramolecular  Change  in  the  Quinole  Series. 

In  the  foregoing  sections  we  have  encountered  one  or  two 
instances  in  which  the  quinole  derivatives  were  converted  into 
benzenoid  compounds  by  the  action  of  suitable  reagents;  in 
the  present  section  we  shall  discuss  several  other  cases  of  the 
same  type. 

It  has  been  shown  by  Stewart  and  Baly1  that  the  intro- 
duction of  substituents  into  the  quinone  nucleus  tends  to  give 
the  intramolecular  vibrations  of  the  system  a  more  and  more 
pronounced  benzenoid  character;  the  compounds  lose  their 
ketonic  properties  to  a  marked  extent,2  and  their  absorption 
spectra  approximate  more  and  more  closely  to  those  of  the  ben- 
zene derivatives.  In  the  case  of  the  quinoles,  the  replacement 
of  the  one  carbonyl  group  of  the  quinone  by  a  tertiary  alcoholic 
radicle  appears  to  produce  an  analogous  effect ;  but  since  in  this 
case  there  is  a  possibility  of  the  substances  undergoing  intra- 
molecular rearrangement,  the  process  is  carried  a  step  further 
than  in  the  simple  quinones,  and  a  wandering  of  radicles  ensues 
Which  actually  produces  true  benzene  derivatives. 

In  the  quinole  group,  the  chief  part  of  the  molecule  which 

1  Stewart  and  Baly,  Trans.  Chem.  Soc.,  1906,  89,  618. 

2  Kehrmann,  Ber.,  1888,  21,  3315;  /.  pr.  Ch.  1889,  39,  399;  40,  257. 


216      RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 

is  involved  in  intramolecular  change  is  the  tertiary  alcoholic 
radicle,  and  in  most  cases  the  methyl  group  in  this  wanders  to 
some  other  part  of  the  six-member  ring.  We  may  now 
describe  several  instances  in  which  this  methyl  radicle  is 
removed  from  its  original  position  and  re-attached  to  the  carbon 
atom  in  the  ortho-position. 

Bamberger1  has  found  that  when  quinoles  such  as  those 
shown  below  are  subjected  to  the  action  of  hydrogen,  or,  better, 
hydroxyl  ions,  they  are  converted  into  homologues  of  hydro- 
quinone,  as  the  f ormulae  indicate : — 

HO        CH3 

X 

HO        CH 

II         II  * 

HO        C.CH3 


O 


In  these  cases,  it  is  clear  that  the  forces  which  bring  about 
the  intramolecular  change  are  of  a  strength  sufficient  to  elimi- 
nate a  hydrogen  atom  from  the  nucleus  and  to  replace  it  by  a 
methyl  radicle.  A  much  more  powerful  action  is  shown  in 
another  case,  which  was  investigated  by  Zincke.2  If  we  treat 
tetrabromo-ethyl-quinole  with  concentrated  sulphuric  acid  in 
the  cold,  we  find  that  hydrobromic  acid  is  eliminated,  and  the 
ethyl  radicle  replaces  the  bromine  atom  which  has  been  driven 
out  of  the  nucleus  : — 

1  Bamberger,  Ber.,  1900,  33,  3618.  2  Zincke,  Sir.,  1901,  34,  253. 


THE    QUINOLES  217 

HO        C2H5  0 

X     ;;'  A- •"'•'• 

Br.G         C.Br       -HBr     Br.C         C .  C2H5 

II          II >  II          II 

Br.C         C.Br  Br.C        C.Br 

v          v     • 

II  II 

0  O 

A  still  more  extraordinary  wandering  is  seen  in  a  case 
mentioned  by  Auwers.1  If  we  heat  quinoles  with  acetic 
anhydride,  they  yield  monoacetates ;  but  if  sodium  acetate  be 
present,  it  is  found  that  a  diacetate  is  formed  in  the  case  of 
those  quinoles  which  have  a  methyl  group  in  the  position  ortho 
to  the  tertiary  alcohol  residue.  Investigation  shows  that  this 
second  acetyl  group  has  entered  the  methyl  radicle ;  so  that  the 
reaction  really  takes  place  in  the  following  stages :  (1)  acety- 
lation  of  the  hydroxyl  group  of  the  quinole ;  (2)  wandering  of 
the  acetate  group  into  the  methyl  radicle  in  the  ortho-position 
to  it ;  (3)  acetylation  of  the  new  hydroxyl  group  formed  by  the 
change  from  the  quinolic  to  the  benzenoid  structure : — 


CH3CO.O.CH 


>H  CH3CO.O 

Auwers,  Per.,  1902,  35,  449. 


218      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

If  we  examine  the  behaviour  of  quinoles  whose  methyl 
group  contains  a  halogen  substituent,  a  fresh  set  of  changes 
is  presented  to  us.  In  the  first  place,  if  we  allow  equimo- 
lecular  quantities  of  caustic  soda  and  quinole  to  interact,  we 
get,  as  Zincke  has  shown,1  an  oxide  of  the  following  type 
formed : — 


HO        CH2Br 

v 


0 CH2 

v 


HC        CH 

II         II 
HC        CH 

v 

II 
O 


4-  NaOH  =  NaBr  +  H20 


HC 


H 


HC        CH 

v 

II 
0 


On  the  other  hand,  if  excess  of  alkali  be  used,  and  if  the 
quinole  contains  a  methyl  radicle  in  the  ortho-position  to  the 
hydroxyl,  the  reaction  takes  another  turn ;  for  the  oxide  reacts 
with  the  solvent  (methyl  or  ethyl  alcohol)  with  the  following 
results : — 


0 CH2  CH30        CH2OH 

\/  \/ 

C  C 

HC        C .  CH3  +  CH3OH  HC        C .  CH3 

II         II  >      II         II         -> 

HC        CH  HC        CH 

\/  \/ 

C  C 


CH2OH 


CH20 ,  CH 


O 


0 


In  special  cases  it  has  been  observed  that  the  methyl 
radicle  remains  attached  to  its  carbon  atom,  while  another 
group  wanders.  For  example,  Auwers 2  finds  that  in  the 

1  Zincke,  Ber.,  1895,  28,  3121 ;  Annalen,  1901,  320,  177  ;  Auwers,  Ber.,  1902, 
35,  451. 

2  Auwers,  Ber.,  1902,  35,  454. 


THE   QUINOLES  219 

nitro-ketones,  the  nitro-group  wanders  sometimes  into  the 
ortho-  and  sometimes  into  the  meta-position,  as  shown  in  the 
following  formulae  : — 


CH3 

\/ 
C 


HC        C .  CH3 

II         II 
CH3.C        C.N02 

v 

II 
0 


N02        CH3 

\/ 
C  CH3 


CH 

II        II  > 

BrC        C.Br 

v 

II 
O 


A  similar  wandering  of  the  quinole  hydroxyl  group  to  the 
meta-position  has  been  observed  in  one  case.1  When  xylo- 
quinole  is  treated  with  alcoholic  sulphuric  acid,  it  is  converted 
into  a  mixture  of  substances  indicated  in  the  formulae  below, 
from  which  it  will  be  seen  that  in  the  one  case  the  methyl 
radicle  has  wandered,  while  in  the  second  case  the  hydroxyl 
group  has  changed  its  position  in  the  ring. 

1  Bamberger,  Per.,  1907,  40, 1895.| 


220      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 


OH.— 


OH 


In  conclusion,  we  may  add  two  instances  in  which  the 
groups  in  the  para-position  to  one  another  are  acted  upon 
simultaneously.  In  the  first  place  we  may  take  the  action  of 
boiling  acetic  anhydride  upon  the  bromo-substituted  quinoles  in 
which  the  bromine  atom  is  in  the  side-chain.  In  this  case  *  a 
loss  of  hydrobromic  acid  takes  place,  but  at  the  same  time 
reduction  occurs,  and  the  final  product  is  the  diacetyl  deri- 
vative of  para-hydroxy-benzyl  alcohol : — 


HO         CH2Br 

v 

HO        CH 


CH3CO .  0 .  CH2 


HC        CH 

\/ 

C 

II 

o 


(CH3CO)20  = 


CH3CO 


+  HBr  +  0 


Again,  Bamberger 2  has  found  that  in  some  cases  the  action  of 
phenylhydrazine  ends  in  the  production  of  azo-compounds,  the 
intermediate  step  being  the  elimination  of  water  between  the 


Auwers,  Ber.,  1902,  35,  450. 


Bamberger,  Ber.,  1902,  35, 1426. 


THE    QUINOLES 


221 


hydroxyl  group  of  the  quinole  and  the  hydrogen  of  the  imino- 
radicle  of  the  hydrazine  nucleus  : — 

HO        CH3 

v 


HO 


H 


HC        CH 

v 

II 
0 


6.  Conclusion. 

From  the  changes  dealt  with  above,  the  reader  will  have 
gathered  something  of  the  extraordinary  lability  of  the  quinole 
nucleus.  There  is  hardly  another  class  of  compounds  which 
shows  such  examples  of  intramolecular  interchange  of  groups ; 
and  at  present  the  only  determining  factor  which  we  can  detect 
underlying  the  quinole  rearrangements  appears  to  be  the 
attempts  of  the  unstable  quinoles  to  revert  to  the  more  stable 
benzenoid  type.  It  seems  clear  that  further  investigation  of 
this  field  might  lead  us  to  an  understanding  of  the  cause  of  the 
stability  which  the  aromatic  series  in  general  exhibits  towards 
most  reagents.  In  the  quinoles  we  apparently  have  a  bridge 
between  the  alicyclic  compounds  on  the  one  hand  and  the 
aromatic  bodies  on  the  other;  and  as  is  the  case  with  most 
intermediate  compounds,  the  quinoles  are  more  reactive  than 
members  of  either  the  aliphatic  or  the  aromatic  series, 


CHAPTER  X 

THE  TRIPHENYLMETHYL   QUESTION 

1.  Introductory. 

ANY  one  who  glances  through  the  journals  of  the  chemical 
world  for  the  last  few  years  must  be  struck  by  the  enormous 
production  of  new  compounds  which  is  at  present  going  on; 
and  if  he  reflects  at  all,  he  will  be  driven  to  ask  himself  what 
criterion  should  be  applied  in  order  to  distinguish  the  really 
important  substances  from  what  we  may  term  the  by-products 
of  synthetic  chemistry.  It  is  perfectly  clear  from  our  experience 
that  the  only  fate  which  can  overtake  the  majority  of  these  new 
compounds  is  that  their  dossiers  will  be  "neatly  tucked  away 
in  Beilstein,  the  Abstracts  published  by  the  various  Chemical 
Societies,  or  in  other  equally  convenient  depositories  of  infor- 
mation." There  they  will  remain  at  best  in  a  dormant  condition, 
waiting  the  time  when  some  Analogie-arbeit  necessitates  a 
knowledge  of  their  properties.  On  the  other  hand,  those  new 
bodies  which  have  any  interest  apart  from  their  melting-points 
soon  become  centres  of  new  research ;  and  the  more  important 
of  them  usually  lead  to  investigations  extending  far  beyond  the 
constitution  and  properties  of  the  original  compound.  For 
example,  the  researches  which  more  than  a  generation  ago  took 
their  rise  in  the  constitution  of  acetoacetic  ester  have  not  yet 
reached  their  final  stages. 

This  ramification  of  interest  has  seldom  been  so  strongly 
marked  within  recent  years  as  in  the  case  of  the  substance 
termed  triphenylmethyl ;  and  it  is  the  rapid  extension  of  the 
field  of  research  in  this  division  of  the  subject  which  makes 
any  treatment  of  the  triphenylmethyl  problem  difficult.  In  the 
present  chapter,  it  will  be  necessary  to  confine  ourselves  as  far  as 
possible  to  the  narrow  question  of  the  constitution  of  triphenyl- 


THE    TRIPHENYLMETHYL    QUESTION  223 

methyl  and  only  to  touch  lightly  upon  the  wider  questions 
which  are  closely  bound  up  with  it. 

The  discovery  of  triphenylin  ethyl  took  its  rise  in  an  attempt 
to  prepare  hexaphenyl-ethane,  which  was  made  by  Gomberg  1 
in  1900.  He  allowed  "  molecular  "  silver  to  act  upon  triphenyl- 
bromo-methane,  and  obtained  a  compound  which  he  naturally 
supposed  to  be  hexaphenyl-ethane,  for  the  reaction  would 
normally  have  taken  the  course  expressed  in  the  formulae 
below  — 


2  C6H5—  C—  Br  +  2Ag      =      2AgBr  +  C6H5—  C—  C—  C6H5 

Celts  Cells 


On  analysis,  however,  the  substance  was  found  to  have  about 
six  per  cent,  too  little  carbon  to  agree  with  the  hexaphenyl- 
ethane  formula  ;  and  further  examination  showed  that  it  could 
not  be  a  hydrocarbon  at  all,  but  must  contain  oxygen. 

This  oxygen  might  have  been  introduced  in  either  of  two 
ways  :  it  might  have  been  imported  through  the  silver  used  in 
the  reaction  ;  or  it  might  have  been  derived  from  the  air.  The 
experiments  were  therefore  repeated,  other  metals,  such  as  zinc 
and  mercury,  being  used  instead  of  silver  ;  and  still  the  resulting 
substance  was  found  to  be  oxygenated.  From  this  it  was  clear 
that  atmospheric  oxygen  was  the  origin  of  the  oxygen  in  the 
end-product;  and  further  experiments  were  made  in  which 
precautions  were  taken  to  exclude  air  from  the  apparatus.  The 
end-product  in  this  case  differed  from  that  which  had  previously 
been  obtained;  and  on  analysis  it  was  found  to  have  the 
composition  corresponding  to  hexaphenyl-ethane. 

An  examination  of  its  properties,  however,  brought  Gomberg 
to  the  conclusion  that  the  substance  which  he  had  obtained 
could  not  be  hexaphenyl-ethane  ;  for  he  had  expected  that  that 
body  would  be  an  extremely  stable  compound,  whereas  his 
synthetic  hydrocarbon  was  very  reactive. 

At  this  point  we  may  give  a  resume  of  the  chief  properties 
of  the  hydrocarbon.  When  first  prepared,  it  is  a  colourless 
crystalline  solid,  which  dissolves  with  great  readiness  in  most 

1  Gomberg,  /.  Amer.  Chem.  8oc.t  1900,  22,  757;  Ber.,  1900,  33,  3150. 


224      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

organic  solvents,  giving  yellow  solutions.  Even  at  zero  it 
reacts  with  iodine  to  form  triphenylmethyl  iodide.  Exposure 
to  the  air  even  for  a  short  time  is  sufficient  to  transform  it  into 
a  peroxide  ;  and  Gomberg  1  has  been  able  to  prove  that  this 
same  peroxide  can  be  produced  by  the  action  of  sodium  peroxide 
on  triphenyl-chloro-methane  (but  not  by  the  spontaneous 
oxidation  of  triphenylmethyl  chloride  or  of  triphenyl  car.binol 
under  the  same  conditions).  From  this  we  may  deduce  that 
the  peroxide  has  the  constitution  — 

C6H5  C6H5 

C6H5—  C—  0—  0—  C—  C6H5 


The  hydrocarbon  forms  double  compounds2  with  ethers, 
esters,  ketones,  nitriles,  or  aromatic  hydrocarbons  (and  amylene), 
the  composition  of  these  substances  corresponding  to  one  mole- 
cule of  ether  (or  of  the  other  substances)  plus  one  molecule 
of  hexaphenyl-ethane.  Gomberg  ascribed  the  formation  of  the 
oxygenated  derivatives  to  the  change  of  the  oxygen  from  the 
divalent  to  the  quadrivalent  condition,  and  formulated  the  con- 
stitution of  the  substances  generally  as  derivatives  of  the 
following  types  :  — 

K          C(C6H5)3       E  C(C6H5)3       K  C(C6H5)3 

V  \o(  ):0/ 

R         C(C6H5)3       K  C(C6H5)3     EO  C(C6H5)3 

C(C6H6)3 

E.C=NX 

C(C6H5)3 

The  fact  that  these  substances  are  actually  compounds  and 
not  simply  mixtures  in  which  the  ether  or  other  body  is 
held  mechanically  is  proved  by  the  fact  that  similar  compounds 
are  formed  with  carbon  disulphide  and  chloroform,  and  these 

1  Gomberg,  Ber.,  1900,  33,  3150. 

2  Ibid.,  1905,  38,  1333,  2447. 


THE    TRIPHENYLMETHYL    QUESTION  225 

latter  bodies  can  be  heated  to  110°C,  in  a  stream  of  carbon 
dioxide  without  giving  up  their  full  content  of  chloroform  or 
disulphide. 

There  is  one  further  point  to  which  we  must  draw  attention, 
though  it  does  not  directly  concern  the  hydrocarbon.  It  has 
been  shown  l  that  the  halogen  salts,  such  as  triphenylmethyl 
chloride,  (C6H5)3C  .  01,  and  triphenylmethyl  bromide,  (C6H5)3C.Br, 
when  dissolved  in  solvents  such  as  liquid  sulphur  dioxide 
which  have  strong  dissociating  power,  have  conductivities  very 
nearly  equal  to  that  of  methylamine  hydrochloride.  This 
proves  that  in  the  yellow  solutions  obtained  in  this  way,  the 
compounds  are  split  up  into  two  ions,  one  of  which  must  be 
(C6H5)3C. 

From  the  data  which  we  have  given  in  the  preceding 
paragraphs,  it  is  clear  that  the  problem  of  the  constitution  of 
Gomberg's  synthetic  hydrocarbon  opens  up  a  wide  field  for 
speculation  ;  and  numerous  attempts  have  been  made  in  recent 
years  to  discover  the  solution.  Four  views  have  at  one  time 
or  another  gained  a  certain  amount  of  support,  and  we  shall 
deal  with  these  in  turn  in  the  succeeding  sections  of  this 
chapter. 

2.  The  Trivalent  Carbon  Hypothesis. 

The  reactions  of  his  synthetic  hydrocarbon  —  which  we  may 
for  the  sake  of  convenience  term  triphenylmethyl  —  led  Gom- 
berg  2  to  put  forward  the  view  that  the  substance  contained  one 
carbon  atom  attached  to  three  phenyl  radicles,  but  having  no 
fourth  radicle  attached  to  it  :  — 


—  C 


The  fourth  valency  of  the  carbon  atom  may  be  supposed  to  be 
free,  or  to  be  absorbed  by  the  residual  valency  of  the  three 
phenyl  groups.  This  conception  of  a  trivalent  carbon  atom  is 
really  not  so  extraordinary  as  it  seems  ;  for  we  might  consider 
that  ethylene  derivatives  contain  two  adjacent  carbon  atoms  of 

1  Walden,  Ber.,  1902,  35,  2018;  Gomberg,  ibid.,  2045.     Compare  Gomberg, 
Ber.,  1905,  38,  1342. 

2  Gomberg,  J.,  Awer.  Chew.  Soc.,  1900,  22,  757;  Ber.,  1900,  33,  3150. 

q 


226      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

this  type,  instead  of  writing  their  structural  formulae  as  we 
usually  do  with  a  double  bond  between  the  two  unsaturated 
carbons. 

In  favour  of  this  constitutional  formula  for  triphenyl- 
methyl  we  may  urge  the  evidence  derived  from  the  reactions  of 
the  substance  with  iodine  and  with  oxygen,  both  of  which  can 
be  expressed  quite  simply  : — 

(C6H5)3C        I        (C6H5)3C .  I 

(C6H5)3C        I     "  (C6H5)3C.I 

(C6H5)3C        0       (C6H5)3C-0 

+  II   =  I 

(C6H5)3C        0       (C6H5)3C-0 

And  we  might  also  adduce  the  simplicity  of  the  formulae  for 
the  double  compounds  of  triphenylmethyl  with  ethers,  ketones, 
nitriles,  etc. 

All  that  this  amounts  to,  however,  is  that  we  can  express 
these  reactions  in  a  straightforward  manner  on  the  assumption 
of  trivalent  carbon.  If  we  can  express  them  equally  con- 
vincingly by  means  of  a  formula  containing  only  quadrivalent 
atoms,  then  we  should  be  entitled  to  reject  the  trivalent 
carbon  view  as  adding  an  unnecessary  assumption  to  our 
usual  ones. 

But  there  are  facts  which  do  not  agree  with  the  trivalent 
carbon  view.     In  the  first  place,  Gomberg  has  shown  that  in 
*    solution  triphenyl  methyl  has  a  molecular  weight  corresponding 
.  to  a  formula — 

2[(C6H5)3C] 

that  is  to  say,  the  molecular  weight  is  that  of  hexaphenyl- 
ethane  or  some  isomer  of  that  substance.  Secondly,  G-oinberg 
and  Cone  l  have  shown  that  the  three  phenyl  radicles  do  not 
possess  identical  properties,  as  they  should  do  if  the  substance 
actually  had  the  triphenylmethyl  structure.  We  need  only 
outline  their  proof  here,  as  we  shall  have  to  return  to  it  in  a 
later  section.  By  subjecting  para-rosaniline  to  Sandmeyer's 
reaction  they  obtained  tri-p-bromo-triphenyl  carbinol,  which, 
by  the  action  of  hydrochloric  acid,  was  transformed  into  tri-p- 
bromo-triphenylmethyl  chloride : — 

1  Gomberg  and  Cone,  Ber.,  1906,  39,  3274. 


THE    TRIPHENYLMETHYL    QUESTION 

Br 


227 


— C— 01 


When  this  substance  was  treated  in  the  usual  way  with  silver, 
it  gave  a  substance  analogous  to  triphenylmethyl.  This  new 
compound  formed  a  peroxide  just  as  triphenylmethyl  does,  and 
therefore  (if  the  trivalent  carbon  idea  be  correct)  we  may  safely 
assume  that  it  is  tri-p-bromo-triphenyl-methyl : — 


Now  the  tri-p-bromo-triphenyl  chloride  was  sealed  up  in  an 
air-free  flask  with  excess  of  molecular  silver,  and  the  whole 
was  shaken  for  a  considerable  time.  At  the  end  of  this,  it  was 
found  that  the  silver  had  removed  all  the  chlorine  (reaction  of 
triphenylmethyl  formation),  but  in  addition  it  had  abstracted  one 
atom  of  bromine  from  the  ring  of  one  of  the  phenyl  groups. 
Since  there  was  excess  of  silver  present,  if  all  the  three  phenyl 
radicles  had  identical  properties  we  should  expect  that  they 


228      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

would  yield  up  their  bromine  simultaneously.  Further,  the 
new  compound  produced  by  the  elimination  of  bromine  was 
not  a  peroxide  similar  to  that  formed  by  triphenylmethyl,  nor 
did  it  yield  such  a  peroxide  when  exposed  to  air.  The  experi- 
ments were  repeated  with  other  halogen  derivatives  of  tri- 
phenylmethyl, and  led  in  these  cases  to  similar  results.  It  is 
thus  shown  :  (1)  That  the  substitution  of  three  bromine  atoms 
in  the  position  para  to  the  "  trivalent  "  carbon  of  triphenyl- 
methyl in  no  way  interferes  with  the  activity  of  the  sutstance  ; 
(2)  further  action  of  silver  eliminates  only  one  of  the  three 
bromine  atoms,  so  that  one  nucleus  differs  from  the  other  two. 
From  (1)  the  complete  analogy  between  triphenylmethyl  and 
its  tribromo-derivative  is  clear  ;  and  hence  we  are  entitled  to 
draw  the  conclusion  that  the  inference  in  (2)  is  valid  also  for 
the  parent  hydrocarbon.  But  if  in  triphenylmethyl  we  have 
one  phenyl  nucleus  endowed  with  properties  not  shared  by  the 
other  two,  it  is  evident  that  a  symmetrical  formula  — 


s  —  C 


cannot  give  a  true  representation  of  the  substance's  properties. 
The  triphenylmethyl  structural  formula  with  trivalent  carbon 
has  therefore  been  abandoned  at  the  present  day. 

3.  The  Hexaphenyl-ethane  Hypothesis. 

When  Gomberg's  hydrocarbon  was  first  prepared,  its  pro- 
perties were  found  to  be  so  different  from  what  had  been 
expected  of  hexaphenyl-ethane  that  the  latter  structure  was  at 
once  dismissed  as  incapable  of  giving  a  proper  representation 
of  the  reactions  of  the  new  substance  ;  but  as  time  went  on, 
and  more  information  with  regard  to  the  properties  of  the  more 
highly  phenylated  ethanes  was  acquired,  it  seemed  as  if  the 
earlier  view  had  been  rather  hasty,  and  that  there  was  a  certain 
amount  of  probability  in  the  idea  that  Gomberg's  compound 
was,  after  all,  merely  hexaphenyl-ethane. 

For  two  years,  however,  this  view  was  kept  in  abeyance, 
owing  to  the  fact  that  Ullmann  and  Borsum  L  had  synthesized 
1  Ullmann  and  Borsum,  Ber.,  1902,  35,  2877  ;  Gomberg,  ibid,,  39H, 


THE    TRIPHENYLMETHYL    QUESTION  229 

a  substance  which  they  regarded  as  hexaphenyl-ethane.  This 
body  was  obtained  by  reducing  triphenyl  carbinol;  and  its 
properties  corresponded  to  some  extent  with  those  which  had 
been  anticipated  for  hexaphenyl-ethane.  In  1904,  however, 
Tschitschibabin  *  established  the  constitution  of  this  supposed 
hexaphenyl-ethane,  proving  it  to  be  a  compound  of  the  follow- 
ing structure- : — 


x  /Cells 

CeHg — C — CsHi — CEL 

Celv 

This  removal  of  the  supposed  hexaphenyl-ethane  from  the 
literature  thus  left  the  possibility  open  that  Gomberg's  tri- 
phenylmethyl really  had  the  hexaphenyl-ethane  structure  ;  and 
Tschitschibabin2  put  this  suggestion  forward,  basing  his  views 
on  the  following  considerations. 

In  the  first  place,  we  have  to  account  for  the  reactivity  of 
triphenylmethyl,  and  show  why  a  compound  of  the  hexaphenyl- 
ethane  structure  should  be  reactive.  Tschitschibabin  pointed 
out  that  an  accumulation  of  electro-negative  atoms  or  radicles 
in  a  molecule  tended  to  make  it  much  less  stable.  We  have 
already  seen  an  example  of  this  in  connection  with  Zincke's 
work  on  the  chlorination  of  phenols ;  the  accumulation  of 
chlorine  atoms  in  the  compound  leads  to  its  degradation  into 
simpler  substances.  Again,  spacial  factors  sometimes  come 
into  play  and  cause  a  saturated  substance  like  trimethylene  to 
behave  as  if  it  were  an  unsaturated  hydrocarbon.  These  con- 
siderations show  that  we  must  be  prepared  for  certain  anomalies 
and  must  beware  of  judging  problems  of  constitution  on  too 
rigid  lines.  Further,  it  is  not  necessary  to  assume  an  unsatu- 
rated structure  for  triphenylmethyl  merely  in  order  to  account 
for  its  ready  reaction  with  :oxygen  to  form  a  peroxide,  for 
Gomberg 3  himself  has  shown  that  the  fully  saturated  analogue 
triphenyl-iodo-methane  reacts  in  a  similar  manner.  A  further 
point  in  favour  of  the  hexaphenyl-ethane  view  is  Gomberg's 
proof  that  in  solution  his  triphenylmethyl  had  a  molecular 
weight  agreeing  with  the  hexaphenyl-ethane  formula  rather 
/  than  with  that  of  tri-phenylmethyl.  Nor  is  this  all;  for 

1  Tschitschibabin,  Ber.,  1904,  87,  4709.  2  Ibid. 

3  Gomberg,  Ber.,  1902,  35,  1836. 


230      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 

when  we  examine  more  carefully  the  behaviour  of  the  highly 
phenylated  ethane  derivatives  we  shall  find  that  they  are 
by  no  means  so  stable  as  analogy  would  lead  us  to  expect. 
Tschitschibabin  l  has  proved  that  even  below  its  melting-point 
pentaphenyl-ethane  is  attacked  by  air;  at  a  temperature  of 
only  150°  C.  hydrochloric  acid  in  benzene  solution  acts  on  it 
so  powerfully  that  the  bond  between  the  two  ethane  carbon 
atoms  is  broken,  and  such  products  as  tetraphenyl-ethane,  tri- 
phenylmethane,  and  triphenyl-chloro-m  ethane,  are  formed; 
while  Cone  and  Kobinson  2  found  that  the  action  of  phosphorus 
pentachloride  in  boiling  benzene  broke  down  the  pentaphenyl 
derivative  into  triphenylmethyl  chloride. 

Against  the  hexaphenyl-ethane  hypothesis  we  may  adduce 
several  arguments.  In  the  first  place,  triphenylmethyl  is  a 
colourless  solid,  but  its  solutions  are  deep  yellow  in  tint  :  no 
ordinary  benzenoid  derivative  is  known  which  behaves  in  this 
way.  Stronger  evidence  is  to  be  found  in  the  work  of  Gomberg, 
which  we  mentioned  in  the  previous  section,  by  which  he 
showed  that  one  phenyl  group  had  properties  different  from 
those  of  the  others.  The  ordinary  hexaphenyl-ethane  formula 
gives  no  indication  of  this.  Thirdly,  Gomberg3  has  proved 
that  his  hydrocarbon  can  easily  be  converted  into  that  which 
was  obtained  by  Ullmann  and  Borsum.  On  the  hexaphenyl- 
ethane  hypothesis,  this  reaction  would  take  the  following 
course,  which  is  parallel  to  that  which  is  taken  in  the 
semidine  change  — 

H 

--  >     (C6H5)3C  .  C6H4  .  CH 


C6H4.H  C6H5 


K .  C6H4 .  NH .  NH .  C6H4 .  H >  E .  C6H4 .  NH .  C6H4.  NH2 

t I 

But  Jacobson,4  the  greatest  authority  on  the  benzidine  and 
semidine  changes,  regards  such  a  change  in  the  triphenylmethyl 

1  Tschitschibabin,  Ber.,  1907,  40,  367. 

2  Cone  and  Kobinson,  Ber.,  1907,  40,  2160. 

•  Gomberg,  Ber.,  1902,  35,  3918  ;  1903,  36,  376. 
4  Jacobson,  Ber.,  1904,  37,  196. 


THE    TRIPHENYLMETHYL    QUESTION  231 

series  as  most  unlikely.  Lastly,  we  have  already  seen  that 
one  of  the  most  marked  characteristics  of  triphenyl methyl 
is  its  capacity  for  forming  double  compounds  with  solvents ; 
but  no  such  property  seems  to  be  possessed  by  compounds 
analagous  to  hexaphenyl-ethane. 

From  the  foregoing  paragraphs,  it  is  clear  that  the  arguments 
both  in  favour  of  and  against  the  hexaphenyl-ethane  view 
depend  to  some  extent  upon  analogy ;  and  we  must  be  careful 
not  to  lay  too  much  stress  upon  them  unless  we  are  satisfied 
that  the  analogies  really  hold  good.  If  we  rule  out  the 
arguments  based  upon  what  a  compound  "  ought "  to  do,  it  will 
be  seen  that  the  evidence  remaining — Gomberg's  differentiation 
between  the  phenyl  nuclei — tells  against  the  hexaphenyl-ethane 
hypothesis. 

4.  Quinonoid  Hypotheses. 

If  we  reject  the  two  hypotheses  which  we  have  dealt  with 
in  the  preceding  sections,  it  is  clear  that  we  have  still  a  third 
possibility  open  to  us ;  for  both  the  triphenylmethyl  view  and 
the  hexaphenyl-ethane  explanation  were  based  on  the  assump- 
tion that  the  phenyl  nuclei  in  triphenylmethyl  were  benzenoid 
in  character,  so  that  by  assuming  a  quinonoid  structure  for  the 
substance  we  shall  arrive  at  totally  different  types  of  formulae. 
The  quinonoid  conception  of  triphenylmethyl  was  put  forward 
very  early  in  the  compound's  history  by  Kehrmann.1 


This   suggestion,   involving   as    it  does  the   assumption  of  a 

1  Kehrmann,  Ber.,  1901,  84,  3818;  see  also  Norris  and  Sanders,  Am.  Chem. 
J.,  1901,  25,  117;  and  Gomberg,  Ber.,  1902,  35,  1824. 


232      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

divalent  carbon  atom,  meets  with  little  approval  at  the  present 
time  ;  and  since  other  formulae  of  the  quinonoid  type  have  since 
been  suggested  which  do  not  necessitate  such  a  postulate,  we 
need  not  deal  further  with  this  one. 

In  1903,  Heintschel  1  proposed  the  formula  below  — 

C6H5x  /CH-CH,  /CH=CHX  /Cells 

)C=C(  )CH—  CH(  )C=CC 

C6H/         XCH=CH/  XCH=CIF          XC6H5 


On  this  hypothesis,  the  first  step  in  the  synthesis  of  triphenyl- 
methyl  is  the  conversion  of  triphenyl-chloro-methane  into  a 
desmotropic  form  in  which  the  chlorine  atom  has  been  shifted 
into  a  position  para  to  the  methane  carbon  atom  — 


C6H5\  /CH=CIL  C6H5v  /CH=CHX      /H 

<  XCH  ->       xc=c  xc 


C6H|  CH—  CH  C6H5  CH-CH         C1 

01 

By  the  action  of  metals,  two  chlorine  atoms  are  withdrawn  from 
two  molecules  of  the  chloro-compound,  and  in  this  way 
triphenylmethyl  is  produced  — 


Civ       /CH—  CHL 

xc  o 

XC6H5 


-  2AgCl 


C6H5\  /CH=CHX  /CH-CHV  /C6H5 

XC=C  XCH—  CH 


C6H5 

An  examination  of  Heintschel'  s  formula  will  show  that  it 
contains  two  quinonoid  phenyl  nuclei,  Jacobson  2  proposed  to 
modify  this,  making  only  one  phenyl  group  quinonoid,  as  shown 
below  — 

C6H5      H         CH-CH  C6H5 

\    \/  \        / 

C6H5—  C—  C  C=C 

C6H5  CH-CH  C6H5 

1  Heintscliel,  Ber.,  1903  ;  36,  320,  579. 

2  JacobeoD,  Ber.,  1901,  37,196. 


THE    TRIPHENYLMETHYL    QUESTION  233 

This  view  makes  triphenylmethyl  a  derivative  of  a  substance 
approaching  the  quinole  type ;  and  as  we  have  already  seen 
that  the  reactivity  of  the  quinoles  is  quite  abnormal,  we  might 
expect  considerable  reactive  power  from  a  body  of  the  structure 
proposed  by  Jacobson.  The  change  of  the  Gomberg  hydrocarbon 
into  the  substance  prepared  by  Ullmann  and  Borsum  can  also  be 
easily  explained  on  this  hypothesis,  as  the  wandering  of  a  single 
hydrogen  atom  is  sufficient  to  account  for  the  isomerization — 

OeHs      H ':  CgHs 

\  I  /f 1  TT  \ 

C6H5— C— /    "\=C  5->C6H5— C- 


The  Jacobson  formula  helps  us  to  understand  the  fact  that  this 
substance,  containing  six  phenyl  radicles,  can  act  as  if  it  had 
the  constitution  of  triphenylmethyl ;  for  if  it  be  assumed  that 
the  molecule  is  decomposed  by  halogens  in  such  a  way  that  the 
single  bond  between  the  quinonoid  nucleus  and  the  adjacent 
carbon  atom  is  loosened,  then  we  should  have  two  "  triphenyl- 
methyl "  radicles  set  free  which  would  at  once  react  with  halogen 
atoms  giving  two  molecules  of  triphenylmethyl  halide.  The 
quinonoid  formula  also  makes  clear  the  meaning  of  the  experi- 
ments of  Gomberg  and  Cone  1  to  which  we  made  reference  in  a 
previous  section.  Let  us  take  for  example  the  case  of  tri-p- 
bromo-triphenylmethyl  chloride — 


-C— Cl 


Br 

Gomberg  and  Cone,^er.,  1906,  39,  3274. 


234      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

it  is  clear  that,  when  it  is  converted  into  triphenylmethyl  by 
the  action  of  metals,  one  of  the  phenyl  radicles  must  become 
quinonoid ;  and  an  examination  of  the  formula  of  the  substance 
which  would  be  formed  if  the  quinonoid  view  be  correct  will 
show  that  one  of  the  halogen  atoms  (marked  with  an  asterisk) 
should  possess  the  properties  of  a  halogen  atom  attached  to  an 
aliphatic  chain  rather  than  those  which  are  shown  by  halogen 
atoms  bound  to  aromatic  nuclei — 


*Br 

\ 

Now,  such  a  halogen  atom  will  be  more  easily  attacked  by 
metals  than  will  be  the  case  with  the  other  bromine  atoms  in 
the  compound  in  question ;  so  that  we  should  expect  that  the 
action  of  an  excess  of,  say,  silver  upon  the  tri-^-bromo-triphenyl- 
methane  chloride  will  result  in  two  reactions,  the  first  of  which 
will  lead  to  the  elimination  of  two  chlorine  atoms,  giving  rise 
to  the  compound  whose  formula  is  shown  above,  while  the 
further  action  of  the  silver  will  remove  two  bromine  atoms 
from  two  molecules  of  this  body,  the  result  being  the  formation 
of  a  substance  having  the  constitution  shown  below — 

(CeEUBr^C^      V7  V"      "Vc(C6H4Br)J 

(C6H,Br)3CX    \— / 


— Bro 


(C6H4Br)2C= 


C(C6H4Br)3  (C6H4Br3C 

The  results  obtained  experimentally  by  Gornberg  and  Cone 
proved  that  one  of  the  phenyl  radicles  did  actually  change  from 
the  benzenoid  to  the  quinonoid  form  ;  but  in  the  view  of  these 
experimenters  the  assumption  of  this  change  alone  was  not 
sufficient  to  account  fully  for  the  problems  which  the  properties 
of  triphenylmethyl  suggest. 

We  must  now  turn  to  examine  the  objections  which  have 
been  brought  against  the  quinonoid  view. 


THE    TRIPHENYLMETHYL    QUESTION  235 

Tschitschibabin 1   points  out  that  one  of  the  most  speedy 
and   apparently   simple  reactions  which   the   triphenylmethyl 
derivatives  undergo  is  the  formation  of  the  peroxide — 
(C6H5)3C— 0-0-C(C6H5)3 

but  that  if  we  are  to  explain  this  according  to  the  Jacobson 
formula  we  should  have  to  assume  an  extremely  complicated 
isomeric  change  as  the  first  step  in  the  process. 

Gomberg  and  Cone 2  draw  attention  to  the  fact  that  Jacobson 
makes  triphenylmethyl  a  derivative  of  a  substance  analogous 
to  a  secondary  quinole — 

H  H 


C(C6H5)3  OH 

But  since  secondary  quinoles  have  not  yet  been  proved  to  be 
capable  of  existence,  these  authors  consider  doubtful  the 
existence  of  compounds  of  the  Jacobson  type.  Furthermore, 
if  we  grant  the  possibility  of  their  existence,  it  is  probable  that 
they  will  behave  like  ordinary  quinoles,  and  hence  their  reactions 
with  acids  should  resemble  to  some  extent  the  rearrangements 
which  quinoles  undergo  under  the  same  conditions.  As  we 
have  seen  in  the  chapter  upon  quinoles,  the  alkyl  group  in 
these  substances  usually  wanders  to  the  ortho-position ;  whence 
by  analogy  the  substance  produced  by  the  action  of  acids  upon 
triphenylmethyl  (Ullmann  and  Borsum's  hydrocarbon)  should 
be  represented  by  the  formula  (I.)  and  not  by  (II.),  though 
Tschitschibabin  believed  that  (II.)  was  formed.  These  arguments, 
as  the  authors  themselves  admit,  are  purely  theoretical,  and 
depend  largely  upon  negative  evidence. 


(C6H5)2CH-<f          >      (C6H5)2CH-4          >-C(C6H5)3 


(I.)  (II.) 

From  a  somewhat  similar  standpoint  Auwers 3  has  criticized 

1  TschitscLibabin,  Ber.,  1905,  38,  771. 

2  Gomberg  and  Cone,  Ber.,  1905,  38,  2455. 

3  Auwers,  Ber.,  1907,  40,  2159. 


236      RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 

the  Jacobson  formula.  He  points  out  that  the  para-methylene 
quinonoid  derivatives  show  such  a  tendency  to  revert  to  the 
benzenoid  structure  that  in  some  cases  a  profound  intramolecular 
change  may  take  place.  For  example,  in  the  compound  (I.) 
below,  the  group  —  CHC12  wanders  from  its  original  position  to 
the  atom  next  the  para-carbon  atom  in  order  to  facilitate  the 
formation  of  the  benzenoid  ring  (II.)  in  preference  to  the 
quinonoid  one  :  — 


v 

/\ 


UH2.CHCla 
(I.)  (II.) 

By  analogy,  it  seems  hardly  likely  that  the  hydrogen  atom 
marked  with  an  asterisk  in  the  Jacobson  formula  would  remain 
fixed  in  its  present  position  when  by  a  similar  wandering  to  the 
para-carbon  atom  it  could  allow  the  compound  to  revert  to  the 
benzenoid  type. 


-CH(C6H5) 


That  such  a  wandering  must  be  possible  is  shown  by  the  con- 
version of  the  Jacobson  compound  into  that  of  Ullmann  and 
Borsum  by  the  action  of  acids;  but  it  seems  strange  that 
a  compound  of  the  Jacobson  formula  should  exist  in  the  free 
state  at  all. 

Against  the  Heintschel  formula,  it  has  been  alleged  by 
Tschitschibabin  *  that  it  should  be  easily  isomerized  into  a 
compound  having  the  structure  (B);  whereas  in  practice  no 
such  change  takes  place. 

1  Tschitscliibabin,  Ber.,  1905,  38,  771. 


THE    TRIPHENYLMETHYL    QUESTION  237 

H 


(C6H5)2CH-<f          >-<<  >-CH(C6H*)2 


From  the  foregoing  summary  it  will  be  seen  that  the  argu- 
ments both  in  favour  of  and  against  the  quinonoid  structure  for 
triphenylmethyl  are  based  very  largely  upon  considerations  of 
what  a  compound  ought  to  do  if  it  has  a  structure  analogous  to 
some  other  compound,  the  latter  body  being  as  yet  undiscovered 
in  practice.  As  far  as  the  relevant  evidence  is  concerned, 
it  certainly  goes  to  show  that  the  quinonoid  formula  is  a  step  in 
advance  of  either  the  triphenylmethyl  hypothesis  or  the 
hexaphenyl-ethane  view. 


5.  The  Tautomerism  Hypothesis. 

We  have  now  exhausted  the  possibilities  of  static  formulse 
to  explain  the  behaviour  of  triphenylmethyl ;  and  it  is  evident 
that  the  results  have  not  been  completely  satisfactory.  All  the 
three  views  which  we  have  discussed  in  the  foregoing  sections 
have  certain  advantages ;  and  each  has  its  own  drawbacks.  It 
thus  becomes  clear  that,  if  we  are  to  make  any  further  progress 
towards  a  solution  of  the  problem,  we  must  contrive  some  means 
of  uniting  the  advantages  of  the  various  formulae ;  while  at  the 
same  time  we  must  endeavour  to  minimize  their  weak  points. 
In  order  to  do  this  it  is  obvious  that  we  must  turn  to  modern 
dynamic  ideas  and  represent  triphenylmethyl  as  a  series  of 
equilibrium  mixtures  of  isomerides. 

Gomberg1  has  developed  this  line  of  thought;  and  if  his 
results  do  not  represent  the  truth,  it  seems  probable  that  they 
come  very  close  to  it.  At  the  present  time  we  cannot  assume 

*  Gomberg,  Ber.,  1907,  40, 1880. 


238      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

that  the  problem  is  completely  solved ;  but  we  are  evidently 
very  near  to  the  solution. 

G-omberg's  later  views  took  their  rise  in  the  fact  that  there 
are  two  varieties  of  triphenylmethyl  which  differ  from  each 
other  in  colour ;  the  solid  form  of  the  substance  is  colourless  ; 
but  in  solution  this  is  changed  into  a  yellow  compound. 
Schmidlin1  states  that  he  has  obtained  the  two  forms  of  the 
substance  in  solution.  Now,  Gomberg  assumes  in  the  first  place 
that  there  are  two  tautomeric  forms  of  triphenylmethyl,  CasHao ; 
and  in  the  second  place  that  the  radicle  triphenylmethyl, 
(C6H5)3C,  can  exist  as  such  and  is  also  capable  of  tautomerization. 
Let  us  now  take  up  the  possible  constitution  of  the  solid, 
colourless  modification.  This  we  may  suppose  to  be  hexaphenyl- 
ethane.  It  is  evident  that  we  may  assume  tautomeric  change 
in  this  compound,  leading  us  to  the  following  structure  : — 


This  alteration  of  the  benzenoid  into  the  quinonoid  form  would 
be  accompanied  by  a  change  of  the  substance  from  colourless  to 
yellow ;  and  since  all  ordinary  solvents  seem  to  be  capable 
of  yielding  yellow  solutions  of  triphenylmethyl,  we  may  assume 
that  this  change  from  the  benzenoid  to  the  quinonoid  form 
takes  place  under  the  action  of  most  solvents  during  the  process 
of  solution. 

We  must  now  go  a  step  further  and  deal  with  the  behaviour 
of  triphenylmethyl  dissolved  in  a  medium  of  high  dissociating 
power,  liquid  sulphur  dioxide.  It  has  been  proved  by  Walden 2 
that  a  solution  of  the  hydrocarbon  in  this  solvent  possesses 
a  fairly  high  conductivity,  and  that  the  molecular  conductivity 
increases  with  the  dilution ;  in  other  words,  the  substance 
behaves  just  like  an  ordinary  ionized  salt.  From  this  behaviour, 
Gomberg  deduces  that  tautomerization  is  not  the  only  change 
which  triphenylmethyl  undergoes  as  it  is  dissolved ;  but  that 
in  addition  it  is  dissociated  into  two  ions  which  we  may 

1  Schmidlin,  Ber.,  1908,  41,  2471. 

2  Walden,  Zeit.  Phys.  Chem.,  1903,  43,  443 ;  Gomberg  and  Cone,  Ber.,  1904, 
37,  2403. 


THE    TRIPHENYLMETHYL    QUESTION  239 

represent   as   below.      The    anion   is   supposed    to  have    the 
benzenoid  structure,  while  the  kation  is  quinonoid. 


/H 


'/ 


H-.+ 


(C6H5)2C :  C6H4^  (Quinonoid) 

(Benzenoid) 
[(G,H^G- 

On  this  view,  the  action  of  iodine  upon  triphenylmethyl  solu- 
tions is  explicable.  The  iodine  in  solution  is  supposed  to 
interact  with  both  the  anion  and  the  kation,  yielding  one 
molecule  of  benzenoid  triphenylmethyl  iodide  and  one  molecule 
in  the  quinonoid  form;  but  since  the  latter  seems  to  be 
incapable  of  existence  in  the  free  state,  it  is  assumed  that  it 
undergoes  intramolecular  change  at  once  and  produces  a 
benzenoid  molecule.  When  we  turn  to  the  action  of  oxygen 
upon  triphenylmethyl  in  solution,  however,  we  have  a  somewhat 
different  state  of  affairs,  since  only  the  anion  unites  with  oxygen. 
(This  follows  from  the  fact  that  the  peroxide  formed  has  the 
benzenoid  structure,  whereas  the  action  of  oxygen  upon  the 
quinonoid  ion  would  give  rise  to  a  highly  complicated  product 
which  is  not  observed  among  the  reaction  products).  We  are 
thus  led  to  the  further  assumption  that  in  the  process  of  peroxide 
formation  the  first  step  is  the  oxidation  of  the  benzenoid  ions ; 
as  these  are  removed  from  the  solution,  equilibrium  is  disturbed ; 
and,  in  order  to  re-establish  it,  some  of  the  quinonoid  ions  must 
re-tautomerize  into  the  benzenoid  form.  They  in  turn  are 
removed  by  the  oxygen ;  and  the  process  continues  until  all  the 
triphenylmethyl  is  exhausted. 

The  same  tautomerization  process  can  be  invoked  to  explain 
why  triphenylmethyl  gives  a  yellow  solution  with  ethers,  esters 
and  ketones,  while  the  solid  double  compounds  which  crystal- 
lize out  from  these  solutions  are  colourless.  In  this  case  the 
benzenoid  ions  may  be  assumed  to  unite  with  the  quadrivalent 
oxygen  of  the  ethers,  etc. ;  and  in  order  to  take  their  place  some 
of  the  quinonoid  ions  are  converted  into  benzenoid  ones. 

According  to  Gomberg,  then,  we  can  explain  all  the  im- 
portant properties  of  triphenylmethyl  on  the  basis  of  the 


240      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

following  hypotheses :  (1)  tautomerization  of  solid  triphenyl- 
methyl  to  a  quinonoid  substance  having  the  Jacobson  formula ; 
(2)  partial  dissociation  of  this  compound  into  positive  and 
negative  ions  in  all  solvents  ;  (3)  mutual  interconvertibility  of 
these  ions  by  tautomeric  change.  Gomberg  further  assumes 
that  solid  triphenylmethyl  is  actually  a  free  radicle,  — C(C6H5)3. 

6.  Conclusion. 

We  have  now  examined  in  turn  the  principal  hypotheses 
which  have  been  put  forward  at  various  times  to  account  for 
the  peculiar  properties  of  triphenylmethyl;  and  it  must  be 
admitted  that  even  yet  there  appears  to  be  some  doubt  as  to 
whether  we  have  arrived  at  the  solution  of  the  problem.  The 
substance  in  its  general  behaviour  is  so  unlike  the  majority  of 
organic  compounds  that  at  first  sight  the  tri-valent  carbon 
hypothesis  appeared  to  have  some  points  in  its  favour  ;  but,  as 
we  have  seen,  the  arguments  against  it  are  strong.  It  seems 
clear  that  the  quinonoid  view,  however  it  be  expressed,  is  the 
most  probable  of  all ;  and,  in  its  final  form  as  put  forward  by 
Gomberg,  it  seems  to  present  the  maximum  of  advantages.  In 
certain  respects  triphenylmethyl  appears  to  resemble  the  quin- 
hydrone  type  of  compound,  and  it  may  be  that  further  re- 
searches in  that  branch  of  the  subject  may  throw  light  upon 
the  curious  behaviour  of  this  enigmatic  body. 


CHAPTEE  XI 

ASYMMETRIC     SYNTHESES     AND     NEW     METHODS     OF     PRODUCING 
OPTICALLY  ACTIVE   COMPOUNDS 

IF  we  pass  a  current  of  carbon  dioxide  into  water  in  which 
sticks  of  magnesium  have  been  immersed,  some  of  the  gas  is 
reduced  to  formaldehyde l ;  and  by  acting  upon  the  latter  with 
calcium  hydrate  solution,2  we  can  produce  fructose — 

CH2OH .  (CH .  OH)3 .  CO .  CH2OH 

A  similar  operation  is  probably  carried  out  in  the  natural 
synthesis  of  fructose  in  plants,  where  the  starting  materials 
are  also  water  and  carbon  dioxide;  but  the  process  in  the 
latter  case  is  evidently  subject  to  some  influence  which  is 
absent  in  our  ordinary  laboratory  reactions,  for  the  naturally 
occurring  fruit  sugar  is  optically  active,  while  that  prepared 
in  the  laboratory  has  no  action  upon  the  plane  of  polarization. 
The  question  now  suggests  itself,  in  what  way  does  the 
mechanism  of  the  reaction  vary  in  such  a  manner  as  to  produce 
results  so  similar  up  to  a  certain  point,  and  yet  so  distinct  from 
one  another  ? 

It  is  at  once  obvious  that  we  cannot  consider  the  organism 
of  the  plant  merely  as  a  peculiar  kind  of  beaker  in  which  the 
reaction  takes  place;  for  if  this  were  so,  there  would  be  no 
difference  between  the  two  reaction  products.  Evidently,  then, 
the  plant  tissues  play  some  part  other  than  merely  containing 
the  interacting  substances;  they  absorb  water  and  carbon 
dioxide  at  their  surfaces,  bring  the  two  compounds  together, 
and  then  in  some  way  assist  them  to  react  with  one  another 
so  as  to  form  fructose.  The  accepted  view  is  that  the  plant 
tissues  combine  with  both  the  carbon  dioxide  and  the  water 
in  the  first  place  to  form  some  unstable  substance,  and  then 

1  Fenton,  Trans.  Chem.  Soc.,  1907,  91,  687. 

2  Loew,  J.  pr.  Chem,,  1886,  33,  321. 

R 


242        RECENT  ADVANCES   IN   ORGANIC   CHEMISTRY 

eliminate  fructose  as  a  decomposition  product.  If  we  accept 
this  view,  the  problem  before  us  becomes  clear  at  once.  In 
the  case  of  our  laboratory  reaction,  we  are  dealing  throughout 
with  a  purely  symmetrical  set  of  substances,  and  there  is  no 
possibility  of  optically  active  products  being  formed.  But  in 
the  case  of  the  plant  we  have  a  mass  of  optically  active  bodies 
which  make  up  the  sap  and  tissues  of  the  organism;  these 
fasten  upon  the  water  and  carbon  dioxide,  combine  with  them, 
forming  more  complex  but  still  optically  active  compounds, 
which  on  decomposition  eliminate  optically  active  products. 

In  recent  years  many  attempts,  some  successful  and  others 
unavailing,  have  been  made  to  parallel  this  process  by  means 
of  our  ordinary  laboratory  reactions.  To  do  this,  we  must 
take  as  our  starting-point  some  optically  active  body  which 
will  play  the  part  of  the  active  constituents  in  the  plant;  to 
this  optically  active  nucleus  we  must  then  add  a  new  chain 
of  atoms,  when  we  shall  have  a  parallel  to  the  unstable  inter- 
mediate product  in  the  plant ;  and  now,  when  we  split  off  the 
new  chain  from  the  original  active  nucleus,  we  must  find  that 
it  in  turn  is  active  if  our  artificial  reaction  is  to  resemble  the 
natural  one.  Perhaps  a  concrete  example  will  make  the  matter 
clearer.  Let  us  take  an  optically  active  acid,  X .  COOH,  and 
combine  it  with  amidobenzaldehyde.  We  shall  then  have  the 
compound — 

X.CO.NH.C6H4.CHO 

To  this  we  then  attach  a  molecule  of  hydrocyanic  acid  to 
form  the  cyanhydrin— 

X .  CO .  NH .  C6H4 .  CH(OH) .  CN 

This  represents  the  intermediate  unstable  product  in  the 
plant;  and  it  will  be  noticed  that  a  new  asymmetric  carbon 
atom  (marked  with  an  asterisk)  has  been  produced  in  the 
compound.  On  hydrolyzing  the  nitrile  group,  we  shall  obtain 
the  corresponding  acid,  in  which  the  new  asymmetric  carbon 
still  remains — 

X .  CO .  NH .  C6H4 .  CH(OH) .  COOH 

If  we  now  wish  to  represent  the  breakdown  of  the  unstable 
plant  product,  we  need  only  split  off  the  original  active  acid 


ASYMMETRIC  SYNTHESES  243 

group  from  this,  and  we  shall  have  left  behind  the  "  new  chain 
of  atoms  " — 

NH2 .  C6H4 .  CH(OH) .  COOH 

Should  this  prove  to  be  active,  the  parallel  between  plant 
synthesis  and  laboratory  reaction  will  be  complete. 

As  far  back  as  18  89,1  evidence  bearing  indirectly  upon  this 
question  had  been  obtained  from  researches  in  the  sugar  group. 
For  example,  it  had  been  shown  that  dextro-mannose  (I.), 
which,  when  submitted  to  the  cyanhydrin  reaction,  should 
theoretically  yield  an  equirnolecular  mixture  of  the  compounds 
(II.)  and  (III.),  actually  in  practice  produces  only  one  of  the 
isomers. 

OHO 
HO.H 
HO.H 
H.OH 
H.OH 
CH2OH  \ 

(I-)   \ 
CHO  /          \    CHO 

HO.H  i  \  H.OH 

HO  .  H  HO  .  H 

HO  .  H  HO  .  H 

H  .  OH  H .  OH 

H  .  OH  H  .  OH 

CH2OH  CH2OH 

(II.)  (III.) 

In  this  case,  therefore,  the  original  asymmetric  nucleus  has 
governed  the  progress  of  the  reaction  to  such  an  extent  as  to 
preclude  the  formation  of  one  isomer.  We  are,  however, 
unable  to  carry  the  matter  further  in  this  particular  example, 
as  we  have  no  means  of  splitting  off  the  original  mannose 
molecule  without  destroying  the  "  new  chain  "  in  the  process. 

Having  now  shown  what  is  being  sought  in  this  branch  of 
the  subject,  it  may  be  well  to  give  at  this  point  a  formal  defi- 
nition of  the  term  "  asymmetric  synthesis"  In  an  asymmetric 
synthesis  an  active  compound  is  taken  as  a  starting-point,  to 
which  a  new  radicle  is  added  in  such  a  way  as  to  form  a  new 
asymmetric  carbon  atom ;  the  originally  active  portion  of  the 

1  Fischer  and  Hirschberger,  Ber.,  1889,  22,  305;  Fischer,  Per.,  1891,  27, 
3208  ;  Fischer,  Annalcn,  1892,  270,  68. 


244       RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

molecule  is  then  split  off,  and  the  remainder  must  be  optically 
active  if  the  synthesis  is  successful. 

We  must  next  review  the  various  attempts  which  have 
been  made  to  solve  this  problem.  The  first  of  any  interest  is 
that  made  by  Cohen  and  Whitely,1  in  which  they  took  as  their 
starting  material  mesaconic  acid.  This  they  esterified  with 
Isevo-menthol,  and  in  this  way  obtained  an  active  ester.  They 
next  reduced  this  to  methyl-succinic  menthyl  ester,  and  finally 
split  off  the  menthyl  group.  If  the  synthesis  had  been  an 
asymmetric  one,  the  remaining  methyl-succinic  acid  should 
have  been  active ;  it  was  not. 

It  is  unnecessary  to  refer  in  detail  to  Fischer  and  Slimmer's 
unsuccessful  method,2  in  which  helicin  was  the  starting-point ; 
or  to  Cohen  and  Whitely's  second  unsuccessful  attempt  to 
produce  optically  active  bodies  in  this  way.3  The  first  true 
asymmetric  synthesis  was  carried  out  by  Marckwald  4  in  the 
following  ingenious  way.  He  took  methyl-ethyl-malonic  acid 
(I.),  which  contains  no  asymmetric  carbon  atom,  and  from  it 
made  the  acid  brucine  salt  (II.).  When  this  salt  is  heated 
until  no  more  carbon  dioxide  is  liberated,  the  brucine  salt  of 
valerianic  acid  (III.)  is  left,  and  it  will  be  noticed  that  this 
acid  contains  a  new  asymmetric  carbon  atom.  Marckwald 
found  that  when  he  liberated  the  valerianic  acid  from  the  salt 
(III.)  it  had  a  slight  optical  rotatory  power,  which  could  only 
be  due  to  the  new  asymmetric  carbon  atom. 

C2H5    COOH        C2H5    COOH  C2H5    H 

V          V  V  • 

/\  /\  /\ 

CH3  COOH     CH3  COO  (Brucine.)  CH3  COO  (Brucine.) 
(I.)  (II.)  (III.) 

By  this  research  it  was  proved  that  asymmetric  synthesis 
was  not  an  impossible  achievement,  and  since  that  time  several 
such  syntheses  have  been  carried  out. 

McKenzie5  has  produced  a  mandelic  ester  in  which  the 

Cohen  and  Whitely,  Proc.  Chem.  Soc.,  1901,  16,  226. 

Fischer  and  Slimmer,  Sitzungsber.  d.  K.  Akad.  Wiss.  Berlin,  1902,  597 ; 
Ber ,  1903,  36,  2575. 

Cohen  and  Whitely,  Trans.  Chem.  Soc.,  1901,  79,  1305. 

Marckwald,  Ber.,  1904,  37,  349,  1368,  4696. 

McKenzie.  Trans.  Chem.  8oc.t  1904,  85,  1249 ;  1906,  89,  365. 


ASYMMETRIC  SYNTHESES  245 

Igevo-form  predominates  over  the  dextro-form.  Choosing  as 
his  starting  substance  benzoyl-formic  acid  (L),  he  esterified  this 
with  laevo-menthol,  producing  the  ester  (II.).  This  he  reduced 
by  means  of  aluminium  amalgam,  and  thus  obtained  mandelic 
Isevo-menthyl  ester  (III.) — 

C6H5 .  CO  .  COOH  C6H5 .  CO  .  COOCi0H19 

(I.)  (II.) 

OH 

C6H5— C— COOC10H19 


(in.) 

On  examination,  (III.)  was  found  to  be  a  mixture  of  c2-man- 
delic-^-menthyl  ester  with  /-mandelic-/-menthyl  ester;  the 
latter  slightly  preponderated  in  the  mixture,  so  that  on  getting 
rid  of  the  menthol,  the  asymmetric  synthesis  would  be  com- 
plete. This  method  has  been  applied  to  the  preparation  of 
active  lactic  from  pyruvic  acid.1 

Using  benzoyl-formic  menthyl  ester  again  as  his  starting- 
point,  the  same  author  2  applied  the  Grignard  reaction,  with 
the  following  result : — 

OMg.I  OH 

C6H5.CO.COOC10H19     C6H5.C.COQC10H19     C6H5.C.COOC10H19 

!  I 

CH3  CH3 

(I.)  (II.)  (III.) 

From  the  menthyl  ester  (I.)  the  compound  (II.)  was  obtained 
by  the  action  of  magnesium  methyl  iodide ;  this  intermediate 
compound  was  then  decomposed  with  water  to  form  (III.); 
from  which  in  turn,  by  the  action  of  acid,  a  mixture  of  exter- 
nally compensated  and  Isevo-methyl-phenyl-glycollic  acid  was 
produced.  Since  the  one  antipode  predominated  over  the  other, 
the  asymmetric  synthesis  had  been  successfully  accomplished. 
McKenzie  and  Wren3  have  been  able  to  synthesize  both 

1  McKenzie,  Trans.  Chem.  Soc.,  1905,  87,  1373 ;  McKenzie  and  Wren,  ibid., 
1906,  89,  688. 

2  McKenzie,  Trans.  Chem.  Soc.,  1904,  85,  1249. 

3  McKenzie  and  Wren,  Trans.  Chem.  Soc.,  1907,  91,  1215. 


246       RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

laevo  and  dextro  forms  of  tartaric  acid  in  the  following  manner. 
Fumaric  acid  was  esterified  with  Isevo-borneol,  the  ester  was 
dissolved  in  glacial  acetic  acid  and  oxidized  with  potassium 
permanganate.  The  result  was  a  tartaric  ester  in  which  there 
was  a  slight  excess  of  the  Isevo  form. 

CH .  COOH         CH .  COOCioHn  CH(OH) .  COOCi0Hi7 

I!  II  I 

CH  •  COOH         CH  •  COOC10H17  CH(OH) .  COOC10H17 

By  using  dextro-borneol  they  obtained  the  dextro-tartaric- 
dextro-borneol  ester  in  excess  over  the  laevo-tartaric-dextro- 
borneol  ester.  When  menthol  was  substituted  for  borneol,  it 
gave  a  greater  yield  of  the  Isevo-tartaric  ester. 

Only  two  other  attempts  in  this  direction  need  be  dealt 
with  here.  In  the  nitrogen  series,  Scholtz 1  has  endeavoured  to 
carry  out  an  asymmetric  synthesis  by  the  action  of  optically 
active  halogen  alkyl  derivatives  upon  racemic  bases  ;  E.  and  0. 
Wedekind 2  have  also  made  experiments  of  the  same  type,  but 
in  neither  case  was  a  true  asymmetric  synthesis  accomplished. 

Smiles 8  investigated  a  case  of  asymmetric  synthesis  of 
tetravalent  sulphur,  but  found  that  when  methyl-ethyl-sulphide 
interacted  with  laevo-menthyl-bromacetate  an  ester  (I.)  was 
produced  which,  on  hydrolysis  with  hydrochloric  acid,  gives  the  ' 
externally  compensated  thetine  (II.).  The  two  antipodes  are 
therefore  formed  in  equal  quantity,  and  no  asymmetric  synthesis 
takes  place. 

CH3     Br  CH3      O 

\/  \/\ 

8  S        CO 

C2H5      CH2.COOC10H19      C2H5      CH2 

(I.)  (ID 

We  must  now  leave  the  question  of  asymmetric  synthesis 
and  consider  some  other  recently  discovered  methods  of 
producing  optically  active  compounds. 

In  his  study  of  the  tartaric  acids,  with  which  modern 
stereochemistry  may  be  said  to  have  begun,  Pasteur  contrived 
three  methods  by  which  optically  active  substances  could  be 

1  Sclioltz,  J5er.,  1901,  34,  3015. 

2  E.  and  O.  Wedekind,  Ber.,  1908,  41,  456. 

3  Smiles,  Trans.  Chem.  8oc.,  1905,  87,  450. 


ASYMMETRIC  SYNTHESES  247 

obtained  from  externally  compensated  mixtures.  One  method 
depended  upon  the  spontaneous  separation  of  the  crystals  of  the 
two  antipodes ;  another  upon  the  selective  action  of  fungi ;  and 
the  third  upon  the  formation  of  salts  with  an  active  substance 
and  the  racemic  compound  as  the  two  components.  No  greater 
tribute  to  Pasteur's  genius  can  be  found  than  the  fact  that  for 
nearly  fifty  years,  in  spite  of  almost  incessant  research  in  this 
field,  no  substitutes  for  these  three  methods  had  been  invented. 
Modifications  may  have  been  introduced,  such  as  substituting 
hydrazone  formation  for  salt  formation,1  but  no  fundamentally 
different  method  was  contrived  until  a  few  years  ago. 

We  may  now  examine  in  turn  the  methods  which  recent 
workers  have  brought  forward.  As  regards  the  question  of 
spontaneous  separation  of  the  antipodes,  no  advance  seems 
possible.  The  study  of  transition  temperatures  has,  of  course, 
rendered  the  use  of  this  mode  of  separation  much  more  certain 
in  its  results  than  it  used  to  be,  but  in  actual  experimental 
details  it  remains  as  Pasteur  left  it.  Numerous  attempts  have 
been  made2  to  modify  it  by  using  optically  active  solvents 
instead  of  symmetrical  ones,  but  none  of  these  have  been 
successful ;  and  it  appears  improbable  that  resolution  can  be 
accomplished  in  this  manner.  It  has  been  shown,3  however, 
that  if  a  saturated  solution  of  a  cW- compound  be  sown  with 
crystals  isomorphous  with  those  of  one  antipode,  that  antipode 
will  predominate  in  the  crystals  formed.  The  seed  crystal  need 
not  necessarily  be  itself  optically  active. 

Turning  now  to  the  biochemical  method  of  separation  by 
the  aid  of  fungi,  though  no  modification  of  this  has  been 
introduced  which  would  enable  us  to  obtain  one  component  of  a 
racemic  substance  by  a  less  wasteful  method  than  the  original 
Pasteur  one,  Bertrand4  has  applied  the  sorbose  bacterium 

1  Erlenmeyer,  junr.,  Her.,  1903,  36,  976;  Erlenmeyer,  junr.,  and  Arnold, 
Annalen,  1904,  337,  307  ;  Neuberg,  Ber.,  1903,  36,  1192  ;  Neuberg  and  Federer, 
Her.,  1905,  38,  801. 

2  Tolloczko,  Zeit.  pliyg.  Chem.,  1896,  20,  412;  Cooper,  ibid.,  1898,  26,  711  ; 
Amer.  Chem.  J.,  1900,  23,  253 ;  Kipping  and  Pope,  Proc.  Chtm.  Soc.,  1898,  14, 113  ; 
cf.  Wedekind,  Ber.,  1908,  41,  457,  footnote  ;  Jones,  Proc.  Cam.  Phil  Soc.,  1907 
14,  27. 

3  Ostromisslensky,  Ber.,  1908,  41,  3035 ;  Kipping  and  Pope,  Trans.  Chem. 
Soc.,  1909,  95,  103. 

4  Bertrand,  C.  r.,  1896,  122,  900;  1898,'  126,  762;  Bull.  soc.  chim.,  1898,  III. 
19,  347,  947, 999. 


248       RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

(Bacterium  xylinum)  in  a  somewhat  different  manner.  This 
bacterium  has  the  faculty  of  oxidizing  certain  hydroxyl- 
compounds,  attacking  secondary  hydroxyl  groups  which  lie  in 
the  a-position  to  a  primary  hydroxyl,  and  transforming  them 
into  carbonyl  groups.  It  is  found,  however,  that  the  configura- 
tion of  the  sugar  submitted  to  the  bacterium  has  a  considerable 
effect  upon  the  action,  for  only  those  sugars  are  attacked  which 
have  the  group  (I,),  those  having  the  group  (II.)  at  the  end  of 
the  chain  being  uninfluenced  by  the  ferment.  It  will  be  seen 
that  in  (I.)  the  two  hydroxyl  groups  are  adjacent,  while  in  (II.) 
a  hydrogen  atom  and  a  hydroxyl  group  lie  together. 

OH  OH  OH  H 


_C— C—  CH2OH  — C — C— CH2OH 

II  II 

H    H  H    OH 

(I.)  (II.) 

For  example,  xylite  is  unattacked  by  the  sorbose  bacterium, 
since  it  does  not  contain  the  grouping  (I.) — 

H   OHH 

CH2OH— C— C— C— CH2OH 

I      I       I 
OHH    OH 

while  arabite,  which  contains  the  grouping  (II.)  is  oxidized  to 
the  corresponding  keto- compound — 

OH  OH  H  OH  H 

-C— C— C— CH2OH->CHoOH— CO— C- 


II  II 

H    OH 


CH2OH-C— C— C— CH2OH->CH2OH— CO— C— C— CH2OH 

I       I      I 
H    H    OH 

Coming  now  to  chemical  methods  of  separating  one 
antipode  from  another,  we  shall  find  that  in  the  last  few  years 
a  very  considerable  number  of  new  lines  have  been  struck  out 
in  this  branch  of  the  subject. 

The  Pasteur  method  of  separating  antipodes  by  means  of 
the  salt  formation  was  in  its  essence  a  purely  static  one.  In 
order  to  resolve  a  racemic  base  into  its  antipodes,  a  salt  was 
made  in  whose  preparation  an  active  acid  was  used.  The  two 
salts  would  then  be,  say,  cZ-acid-d-base  and  d-acid-/-base ;  and 


ASYMMETRIC  SYNTHESES  249 

since  they  were  now  no  longer  optical  antipodes,  they  could  be 
separated  from  one  another  by  utilizing  their  differences  in 
solubility.  This  was  a  purely  physical  method,  in  which  the 
chemical  reaction  played,  per  se,  no  part  in  the  actual  sifting  of 
one  compound  from  the  other. 

Fischer1  attacked  the  matter  from  quite  a  different  stand- 
point. For  him,  the  chemical  reaction,  instead  of  being  a 
subsidiary  part  of  the  separation,  became  the  actual  machinery 
of  resolution.  Taking  the  case  of  the  hydrolysis  of  cane-sugar, 
he  applied  an  asymmetric  hydrolyzer,  and  hoped  in  this  way 
that  a  selective  hydrolysis  might  be  achieved.  Unfortunately, 
his  experiments  with  dextro-  and  Isevo-camphoric  acids,  as  well 
as  others  with  camphor-sulphonic  acids,2  were  alike  unsuccess- 
ful ;  no  selective  hydrolysis  could  be  observed,  both  agents 
hydrolyzing  the  sugar  with  the  same  velocity.  More  interesting 
results  were  obtained  by  Fischer3  in  studying  the  action  of 
enzymes  on  glucosides.  Selective  hydrolysis  takes  place  in 
this  case,  and  thus  a  separation  of  isomers  is  possible. 

A  further  step  in  this  direction  was  taken  by  Marckwald 
and  McKenzie.4  Since  the  reaction  of  salt-formation  is  ionic, 
it  takes  place  almost  instantaneously,  and  spacial  influences 
appear  to  have  very  little  bearing  upon  it.  On  the  other  hand, 
a  comparatively  slow  reaction,  like  esterification,  which  seems 
to  require  the  formation  of  an  unstable  intermediate  product, 
should  lend  itself  better  to  selective  action.  Marckwald  and 
McKenzie  proceeded  on  this  assumption,  and  carried  out  a 
series  of  experiments  in  which  they  esterified  a  racemic  acid 
with  an  active  alcohol,  interrupting  the  process  before  all  the 
acid  was  esterified.  In  this  way,  if  one  antipode  reacted  more 
rapidly  than  the  other  with  the  alcohol,  an  excess  of  its  ester 
would  be  formed.  This  was  found  actually  to  be  the  case 
Lsevo-menthol  reacts  more  readily  with  dextro-  than  with 
laevo-mandelic  acid,  so  that  if  the  esterification  process  be 
interrupted  when  half  the  acid  is  esterified  the  ester  will 
contain  some  Z-mandelic-Z-menthyl  ester  mixed  with  an  excess 
of  d-mandelic-/-menthyl  ester.  By  saponifying  the  mixed  esters 
and  repeating  the  process  several  times  one  antipode  could 

1  Fischer,  Zeit  physiol  Chem.,  1898,  26,  83. 

2  Caldwell,  Proc.  Roy.8oc.,19Ql,  74, 184. 

3  Fischer,  Zeit.  physiol.  Chem.,  1898,  26,  83. 

4  Marckwald  and  McKenzie,  Per.,  1899,  32,  2130. 


250       RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

be  separated  completely  from  the  other.  The  same  authors  1 
applied  the  inverse  method  of  completely  esterifying  the 
racemic  mandelic  acid  with  active  menthol  and  then  fraction- 
ally hydrolyzing  the  mixed  esters  with  insufficient  alkali. 
The  ester  of  the  type  d-acid-/-menthol  is  hydrolyzed  at  a 
different  rate  from  the  type  Z-acid-Z-menthol,  so  that  the  reaction 
product  contains  an  excess  of  one  acid  over  the  other.  By 
removing  the  unhydrolyzed  esters  the  mixture  of  acids  is  left ; 
and  this  was  found  to  be  optically  active. 

Marckwald  and  Meth2  have  applied  a  similar  method  to  the 
case  of  amide  formation.  They  have  shown  that  if,  when  a 
racemic  acid  is  converted  into  an  amide  by  heating  it  with  an 
active  amine,  the  process  be  interrupted  before  all  the  acid 
is  converted  into  amide  the  unconverted  acid  is  optically  active. 
Eacemic  mandelic  acid,  for  example,  when  heated  with  laevo- 
menthylamine  to  160°  or  170°  for  ten  hours,  yields  about 
36  per  cent,  of  amide.  The  remaining  64  per  cent,  of  the  acid 
had  a  specific  rotation  of  [a]D  =  -  5'1°.  It  appears  that 
the  relative  velocities  of  amide  formation  from  Isevo-menthyl- 
amine  with  dextro-  and  laevo-mandelic  acids  are  in  the  ratio 
1  :  0-682. 

Marckwald  and  Paul 3  have  utilized  another  property  of  non- 
antipodic  isomers.  They  take  a  racemic  acid,  form  a  salt  with 
an  active  base  in  the  usual  manner,  and  then  heat  the  salt  to  a 
high  temperature  for  some  time.  Now,  while  two  optical 
antipodes  have  exactly  equal  velocities  of  racemization,  two 
salts  of  the  types  c?-acid-e?-base  and  /-acid-^-base  will  racemize 
at  different  speeds;  so  that  when  the  reaction  product  is 
isolated  and  the  acids  regenerated  they  will  be  found  to  be 
optically  active.  In  many  cases,  however,  this  method  yields 
no  results,  doubtless  owing  to  the  slight  difference  between  the 
racemization  velocities  of  the  two  isomers. 

We  may  now  turn  to  some  other  attempts  which  have 
been  made  to  obtain  optically  active  substances  from  inactive 
compounds.  We  have  already  seen  that  it  has  not  been  found 
possible  to  separate  one  antipode  by  crystallization  from  an 
optically  active  solvent.  There  still  remains  the  possibility 

1  See  also  McKenzie  and  Thompson,  Trans.  Chem.  Soc.,  1905,  87,  1001. 

2  Marckwald  and  Meth,  Ber.,  1905,  38,  801. 

3  Marckwald  and  Paul,  Ber.,  1905,  38,  810 ;  1906,  39,  3C54. 


ASYMMETRIC  SYNTHESES  251 

that  if  we  start  with  an  inactive  substance  containing  no 
asymmetric  carbon  atom  and  so  modify  it,  as  in  asymmetric 
synthesis,  that  an  asymmetric  carbon  atom  is  formed  in  it,  and 
if,  further,  we  carry  out  the  production  of  this  new  asymmetric 
carbon  atom  in  an  active  solvent,  we  might  find  that  the  solvent 
had  had  an  influence  upon  the  reaction  and  caused  the  one 
antipode  to  be  formed  in  excess  of  the  other.  Kipping 1  has 
put  this  idea  to  the  test  in  the  following  way.  He  reduced 
pyruvic  acid  to  lactic  acid  in  a  strong  glucose  solution ;  and 
also  synthesized  benzoin  from  benzaldehyde  and  potassium 
cyanide,  using  as  solvent  a  solution  of  camphor  in  alcohol. 
In  neither  case  was  the  reaction  product  active. 

Hitherto  we  have  dealt  exclusively  with  the  chemical  side 
of  the  problem,  but  it  may  not  be  amiss  to  say  a  few  words 
on  some  experiments  which  have  treated  the  matter  from  a 
physical  point  of  view,  and  have  led  in  some  cases  to  results  of 
considerable  interest. 

Pasteur  appears  to  have  been  the  first  to  attempt  to  produce 
optically  active  substances  by  use  of  a  strong  magnetic  field. 
His  experiments  were  unsuccessful,  as  were  those  of  Boyd.2 
It  appears  that  an  ordinary  magnetic  field  is  not  truly  asym- 
metrical ;  and  in  order  to  introduce  the  required  asymmetry 
some  addition  must  be  made  to  the  play  of  forces  involved. 
Meyer3  contrived  the  following  system  in  order  to  overcome 
this  difficulty.  In  his  apparatus,  a  magnetic  field  is  obtained 
in  the  usual  way,  and  through  it  is  passed  a  ray  of  light.  When 
this  ray  of  light  is  polarized  before  being  passed  through  the  field, 
the  system  becomes  asymmetrical.  Meyer  placed  a  glass  beaker 
in  the  path  of  the  ray,  and  in  the  beaker  he  reduced  benzoyl- 
formic  to  mandelic  acid.  The  results,  however,  were  negative ; 
the  mandelic  acid  formed  being  the  ordinary  externally  com- 
pensated variety.  Though  this  experiment  failed,  the  method 
appears  to  be  based  upon  sound  principles,  for  Cotton 4  has 
shown  that  ^-circularly  polarized  light  is  differently  absorbed 
by  the  dextro-  and  Isevo -forms  of  tartaric  acid.  Absorption 
cannot  be  carried  on  without  a  loss  of  energy,  so  that  obviously  a 

1  Kipping,  Proc.  Chem.  Soo.,  1901,  16,  226 ;  E.  and  O.  Wedekind,  Per.,  1908, 
41,  456. 

2  Boyd,  "  Dissertation;"    Heidelberg,  1896. 

3  Meyer,  Chem.  Zeit.,  1904,  28,  41. 

4  Cotton,  Ann.  Ghim.  Phys.,  1896,  VII.,  8,  373. 


252       RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

reaction,  carried  out  under  polarized  light,  favours  the  forma- 
tion of  one  antipode  rather  than  the  other.  Henle  and  Haakh l 
have  pointed  out  that  results  could  be  expected  from  such  a 
method  only  if  the  reaction  producing  the  asymmetric  carbon 
atom  were  one  which  is  influenced  by  light  action  ;  but  their 
experiments  in  this  line  were  unsuccessful.  Unfortunately, 
the  only  apparatus  at  present  at  the  command  of  the  chemist 
does  not  allow  us  to  influence  reactions  in  this  manner ;  and 
until  we  have  more  powerful  instruments  at  our  disposal  it  is 
unlikely  that  syntheses  in  this  way  will  yield  any  great  results. 
In  conclusion,  we  may  sum  up  the  matter  simply.  The 
task  of  producing  a  laboratory  parallel  to  plant  syntheses  has 
been  accomplished;  we  may  not  have  actually  produced  the 
same  substances  as  the  plant  forms  within  its  organism,  but  we 
have  certainly  utilized  analogous  methods,  and  obtained  similar 
results. 

1  Henle  and  Haakh,  Ber.,  1908,  41,  4261. 


CHAPTER  XII 

SOME   THEOKIES   OF   ADDITION  KEACTIONS 

WHEN  two  compounds  interact  with  one  another  there  are  two 
possible  courses :  in  the  one  case  from  the  two  original  mole- 
cules we  may  have  two  or  more  new  molecules  formed ;  while 
in  the  second  case  the  two  molecules  coalesce  to  form  a  single 
substance.  The  latter  type  of  interaction  is  what  we  understand 
by  the  term  "addition  reaction." 

The  importance  of  addition  reactions  from  the  point  of  view 
of  theory  has  been  very  widely  recognized,  as  is  testified  by  the 
flood  of  hypotheses  which  have  been  put  forward  in  this  branch 
at  one  time  or  another.  We  cannot  attempt  to  give  a  complete 
sketch  of  the  various  views  which  have  been  suggested,  and 
must  content  ourselves  with  brief  accounts  of  several  recent 
attempts  to  formulate  the  principles  underlying  the  practical 
side  of  the  subject.  The  relation  between  stereochemical  in- 
fluences and  the  products  of  addition  reactions  lies  outside  the 
province  of  the  present  volume;  and  we  shall  confine  our 
attention  to  the  purely  structural  side  of  the  question. 

There  is  very  little  connection  between  the  views  which 
different  authors  have  brought  forward  to  deal  with  the  addition 
question,  and  consequently  it  is  difficult  to  arrange  the  various 
theories  in  anything  resembling  logical  sequence.  The  most 
simple  arrangement  seems  to  be  to  begin  with  the  more  general 
views,  and  deal  later  with  those  of  more  restricted  scope ;  and 
this  plan  will  be  followed  in  the  rest  of  the  chapter. 

The  most  general  view  of  all  has  been  taken  by  Michael.1 
According  to  him,  addition  is  caused  by  the  affinity  of  the  two 
interacting  molecules  for  each  other,  and  takes  place  in  the 
manner  which  produces  the  most  "  chemically  saturated  "  com- 
pound. But,  as  he  points  out,  this  "  neutralization  "  of  affinity 

1  Michael,  /.  pr.  Chem.,  1888,  II.  37,  524;  1899,  60,  286,  409;  1903,  68, 
487;  Ber.,  1906,  39,2138. 


254       RECENT  ADVANCES   IN  ORGANIC  CHEMISTRY 

depends  very  largely  upon  the  character  of  the  atoms  forming 
the  two  interacting  molecules.  For  instance,  suppose  that  the 
two  molecules — 

A— B  C— D 

are  capable  of  reacting  together.  Let  us  first  consider  the 
affinity  of  A  for  C  and  for  D.  If  the  affinity  of  A  for  C  is 
greater  than  that  of  A  for  D,  then  we  should  expect  to  find  A 
attaching  itself  to  C,  and  leaving  B  to  attach  itself  to  D,  thus 
forming  the  compound — 

A     B 


L 


D 

But  this  leaves  out  of  account  the  attraction  of  B  for  C.  If 
this  were  greater  than  the  attraction  of  B  for  D,  then  we  should 
expect  the  formation  of  the  compound — 

B     A 

I       I 
C— D 

It  is  obvious  that  the  actual  result  of  the  reaction  will 
depend  upon  the  relative  intensity  of  the  forces  between 
A  and  C  and  between  B  and  C,  coupled  with  the  relative 
intensity  of  the  forces  between  A  and  D  and  between  B  and  D. 
Let  us  represent  the  forces  between  A  and  C  by  ac  and  those 
between  B  and  C  by  lc,  also  those  between  A  and  D  by  ad  and 
those  between  B  and  D  by  Id.  Then  the  forces  which  are 
favouring  the  formation  of  the  first  type — 

A     B 

I       I 
C— D 

(I.) 

will   be   represented   by  ac  +  Id,  while   those   favouring  the 
formation  of — 

B     A 

I       i 
C— D 

(II.) 

will  be  represented  by  be  -f  ad.     The  amounts  of  the  two  com- 
pounds formed  during  the  progress  of  the  reaction  will  therefore 


SOME    THEORIES    OF  ADDITION  REACTIONS      255 

be  to  one  another  in  the  ratio  of  ac  4-  "bd  :  lc  +  ad.     This  is 
termed  Michael's  "  Distribution  Principle."  — 

The  consideration  of  a  concrete  case  will  make  the  matter 
clearer.  Suppose  we  take  propylene,  CH3 .  CH :  CH2,  and  allow 
it  to  react  with  hydriodic  acid.  Two  possible  products  may 
result ;  for  in  the  one  case  the  iodine  atom  may  attach  itself  to 
the  middle  carbon  atom,  while  in  the  other  it  may  be  attracted 
by  the  end  carbon  atom. 

(I.)  (IT.) 

CHa.CHI.CHa  CH3 .  CH2 .  CH2I  (300:1) 

It  has  been  found  that  about  three  hundred  times  more  of  (I.) 
is  formed  than  (II.).  This  is  due  to  the  great  chemical  difference 
between  the  hydrogen  and  iodine  atoms  of  hydriodic  acid.  But 
if  we  lessen  this  difference  between  the  two  atoms  by  substituting 
a  chlorine  atom  for  hydrogen  (using  iodine  chloride  instead  of 
hydriodic  acid),  we  shall  find  that  the  iodine  atom  now  attaches 
itself  to  the  end  of  the  chain  rather  than  to  the  central  atom,  the 
amounts  of  the  compound  (la.)  and  (Ha.)  being  formed  in  the 
ratio  of  three  to  one — 

(la.)  (lla.) 

CH3 .  CHOI .  CH2I  CH3 .  CHI .  CH2C1  (3 : 1) 

The  directing  influences  at  work  may  be  still  further  neutra- 
lized if  we  employ  bromine  chloride  instead  of  iodine  chloride. 
In  this  last  case  there  is  great  similarity  between  the  two  atoms, 
and,  as  a  result,  the  two  possible  end-products  are  formed  in 
very  nearly  equal  proportions  (1.4:1.0) — 

(16.)  (IK.) 

CH3 ,  CHOI .  CH2Br  CH3 .  CHBr .  CH2C1  (1.4 : 1) 

It  will  be  seen  that  the  "  Markownikoff  Eule  " 1  is  only  a 
particular  application  of  the  "  Distribution  Principle,"  and  that 
its  applicability  depends  to  some  extent  upon  the  constitution 
of  the  molecule  containing  the  double  bond.- 

"We  must  now  turn  to  the  views  of  Vorlander.2  If  we  take 
an  a/3-unsaturated  ketone  and  allow  it  to  react  with  an  acid, 
the  first  substance  formed  is  a  coloured,  unstable  substance. 

1  See  p.  58,  footnote. 

2  Vorlander  and  Mumme,  Ber.,  1903,  36,  1470;  Vorlandcr  and  Hayakawa, 
ibid.,  3528;  Vorlaiider,  Annakn,  1903,  341,  1 ;  1906,  345,  155. 


256      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

This  series  of  bodies  Vorlander  designated  as  Type  ^t.  These 
compounds  may  undergo  a  change,  being  converted  into  white 
stable  substances  which  Vorlander  classes  together  under  the 
heading  Type  <$J.  According  to  Vorlander,  these  two  series  of 
substances  differ  from  each  other  in  the  following  way. 

If  we  consider  different  states  of  unsaturation  as  the  outcome 
of  the  different  capacities  of  the  elements  and  radicles  for 
positive  or  negative  electricity  (of  course  this  is  merely  used  as 
an  analogy),  then  in  the  case  of  the  addition  of  two  oppositely 
charged  compounds  there  are  two  possibilities — 

A.  There  may  be  no  complete  neutralization  of  the  electric 
charges.      In   this   case   the   electricity  which   was  originally 
spread  over  the  surface  of  the  substances  becomes  concentrated 
into  a  comparatively  small  area  by  the  attraction  of  the  opposite 
charge  on  the  second  substance,  and   consequently  strain  is 
set  up. 

B.  The  compounds  unite  together  and  become  discharged. 
The  figures  below  illustrate  this  graphically. 


B 


Let  us  take  the  case  of  the  addition  of  an  acid  HX  to  the 
ketone  K.CH:CH.  CO.R  as  an  example.  In  compounds  of 
Class  &  the  acid  HX  has  simply  attached  itself  to  the  ketone 
to  form  a  kind  of  double  compound,  which  he  represents 
thus — 

(HX) 
K.CH CH.CO.K 

Here  no  separation  of  HX  into  H  and  X  occurs.  But  in 
the  case  of  the  stable  bodies,  Type  33,  this  dissociation  of  the 
acid  molecule  does  actually  take  place,  so  that  we  may  write 
the  formula  of  these  bodies  thus — 


SOME    THEORIES    OF  ADDITION  REACTIONS      257 

X      H                                                  H      X 
K .  CH-      -CH  .  CO  .  E         or        E .  CH CH  .  CO.  E 

Now,  in  order  that  any  addition- compound  be  formed  there 
must  exist  between  the  two  interacting  molecules  of  acid  and 
ketone  a  difference  which  Vorlander  terms  a  difference  in 
"  potential."  The  amount  of  this  difference  we  can  estimate  by 
measuring  the  velocity  with  which  the  two  substances  unite ; 
for  the  greater  the  difference  in  potential  between  them,  the 
more  rapidly  will  they  unite  with  each  other.  The  rapidity  of 
formation  of  the  coloured,  unstable  products  is  almost  instan- 
taneous, while  the  rate  of  formation  of  the  stable  type  is  quite 
measurable.  From  this  we  may  conclude  that  the  strain  in  the 
case  of  the  formation  of  the  unstable  bodies  is  greater  than  that 
in  the  production  of  the  stable  isomers. 

Vorlander  expresses  his  view  somewhat  as  follows.  If  we 
consider  the  case  of  two  substances  about  to  interact,  the 
difference  in  potential  between  them  may  be  called  Ji.  When 
the  unstable  compound  is  formed,  only  a  very  little  energy  is 
used  up,  and  the  difference  in  potential  between  the  two 
components  sinks  to  ha,  the  rest  of  the  original  energy  being 
utilized  in  holding  the  two  components  loosely  together.  Since 
there  is  little  change  of  potential  throughout  the  system,  such 
reactions  can  take  place  rapidly  even  at  low  temperatures.  In 
the  case  of  the  stable  compounds,  however,  the  difference  in 
potential  h  is  much  reduced,  say  to  hb.  On  Vorlander's  view, 
time  is  required  to  bring  about  this  change  in  potential,  and 
also  to  overcome  certain  reaction  difficulties,  so  that  the  rate  of 
addition  is  slow.  Further,  the  two  types  of  addition  products, 
owing  to  the  difference  in  potential  between  them,  have  quite 
different  properties.  Vorlander  groups  the  whole  series  of 
addition  reactions  according  to  their  results,  and  in  this  way 
obtains  the  following  series :  (1)  Compounds  of  Type  gl ;  (2) 
double  salts  ;  (3)  complex  salts  ;  (4)  compounds  of  Type  23. 

The  difference  between  the  two  systems  gl  and  23  is 
especially  marked,  when  we  take  into  consideration  the  nature 
of  the  solvent.  In  the  case  of  gl  the  dielectric  constant  of  the 
solvent  will  exercise  a  very  marked  influence ;  but  in  the  case 
of  23,  since  the  compounds  are  in  actual  contact,  the  solvent  will 
have  no  effect. 

In  the  foregoing  theories  the  question  of  addition  was  treated 

0 


258      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

from  a  broad  standpoint,  but  now  we  must  come  to  more 
restricted  fields.  It  is  very  seldom  that  any  theory  is  accepted 
immediately  after  being  published ;  usually  a  considerable  time 
is  required  during  which  the  chemical  world  assimilates  the 
author's  views  in  a  more  or  less  unconscious  manner,  until  some 
day  they  find  their  way  into  text-books.  It  is  a  remarkable 
tribute  to  the  value  of  Thiele's  theory,  with  which  we  are 
about  to  deal,  that  it  became  a  classic  almost  as  soon  as  it  was 
published ;  and  was  not  forced  to  undergo  the  process  of  cud- 
chewing  which  is  usually  the  most  that  can  be  expected  when 
a  new  theory  is  under  consideration. 

The  Thiele  theory l  is  based  upon  the  following  assumption. 
If  we  imagine  the  case  of  a  double  bond  between  two  atoms,  it 
is  supposed  that  the  whole  of  the  affinity  of  the  atoms  is  not 
used  up,  but  that  in  addition  to  that  which  is  utilized  in  join- 
ing the  two  atoms  together  there  is  a  slight  excess  on  each 
atom.  This  slight  excess  of  valency  Thiele  designates  by  the 
name  Partial  Valency,  and  to  its  presence  he  attributes 
the  additive  power  which  unsaturated  compounds  display. 
To  represent  the  partial  valencies,  Thiele  employs  a  dotted  line, 
thus — 

H                               E 
R.C E.C R.N 

II  II  II 

R.C 0 E.N 

H 

Now,  when  we  come  to  the  consideration  of  such  a  system  as 
R.CH:CH.CH:CH.R 

we  find  that  it  shows  one  peculiar  property  in  connection  with 
addition  reactions.  Since  it  contains  two  double  bonds,  it 
might  be  expected  to  take  up  four  atoms  of  hydrogen  or 
bromine  at  once,  or  at  least  to  take  up  two  atoms  of  bromine 
or  hydrogen  at  one  of  the  double  bonds.  In  other  words,  we 
should  expect  to  find  one  molecule  of  bromine  attacking  it  first 
with  the  formation  of  the  compound — 

R.  CHBr .  CHBr  .  CH:  CH.  R 

1  Thiele,  Annalen,  1899,  306,  87. 


SOME    THEORIES   OF  ADDITION   REACTIONS      259 

to  which  another  bromine  molecule  might  be  added,  giving  the 
tetrabromo-compound — 

K .  CHBr  .  CHBr .  CHBr .  CHBr .  R 

In  practice,  however,  the  first  molecule  of  bromine  does  not 
attack  either  of  the  double  bonds ;  it  attacks  them  both  at  once, 
with  the  formation  of  the  compound — 

R. CHBr. CH:CH. CHBr. R 

in  which  both  of  the  original  double  bonds  have  disappeared, 
giving  rise  to  a  new  double  bond  in  the  centre  of  the  molecule. 
If  we  write  out  the  scheme  of  partial  valencies  for  the  original 
substance — 

R.CH:CH.CH:CH.R 


it  is  evident  that  only  the  two  at  the  ends  of  the  system  have 
the  faculty  of  attracting  bromine,  the  two  middle  partial 
valencies  failing  to  act.  In  order  to  express  this  behaviour 
Thiele  writes  the  formula  in  the  following  way,  in  which  the 
two  central  partial  valencies  are  supposed  to  have  neutralized 
one  another : — 

R-CH=CH— CH-CH— R 


We  can  make  this  behaviour  clear  by  supposing  that  the 
carbon  atoms  of  the  chain  are  charged  alternately  with  positive 
and  negative  forces,  the  two  central  atoms  will  then  neutralize 
one  another,  leaving  the  ends  still  charged — 

+      -      +      -  + 

R.CH:CH.CH:CH.R  R.CH:CH.CH:CH.R 

Such  a  system  Thiele  terms  a  Conjugated  Double  Bond. 

If  addition  takes  place  in  the  case  of  a  conjugated  double 
bond,  obviously  the  two  new  atoms  will  attach  themselves  at  the 
ends  of  the  chain  in  the  position  indicated  by  the  free  partial 
valencies.  But  this  does  not  end  the  matter,  for  no  sooner  has 
addition  taken  place  than  the  conjugation  is  destroyed,  and 
hence  a  new  double  bond  will  be  formed  between  the  central 
atoms  of  the  system — 


260      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 
K .  CH  :  CH .  CH  :  CH  .  E  E .  CH  :  OH .  CH  :  CH .  R 

Br— Br  Br  Br 

E.CH.CHrCH.CH.E 

I        1         I        I 
Br  Br 

The  most  striking  application  of  the  Thiele  theory,  however, 
is  found  in  the  case  of  the  benzene  ring.  If  we  write  down  the 
Kekule  formula  for  benzene,  and  fill  in  the  partial  valencies  in 
the  usual  way,  we  arrive  at  the  following  figure  :— 


An  examination  of  this  system  will  show  that  it  forms 
a  closed  series  of  conjugated  double  bonds.  In  other  words,  it 
can  be  written  as  shown  below,  and  no  free  partial  valencies 
exist  in  the  system.  Hence  the  impossibility  of  producing 
addition  products  with  benzene  under  ordinary  conditions. 


Though  the  theory  of  partial  valencies  has  very  widespread 
application,  it  is  not  absolutely  accurate,  for  several  cases  are 
known  in  which  it  is  not  in  accordance  with  the  results  of 
experiment.  We  may  mention  one  or  two  of  these,  without 
laying  too  much  stress  upon  them. 

Harries  *  has  shown  that  unsaturated  aldoximes  or  ketoximes 
may  be  reduced  to  unsaturated  amines.  Thiele  himself  mentions 
a  case  observed  by  Bredt  and  Kallen 2  in  which  hydrocyanic 

1  Harries,  Annalen,  1903,  330,  185. 
9  Bredt  and  Kallen,  Annalen,  293,  338. 


SOME    THEORIES    OF  ADDITION  REACTIONS      261 

acid  adds  on  to  cinnamylidene-malonic  acid  by  simple  addition 
to  the  double  bond  next  the  carboxyl  radical.  Hinrichsen  and 
Lohse  observed  that  when  cinnamenyl-cyanacrylic  ester  (I.) 
is  allowed  to  react  with  bromine  it  yields  a  bromide  of  the 
formula  (II.)  shown  below — 

ON 

(I.)        C6H5.CH:CH.CH:C 

^  OOEt 

ON 


(II.)      C6H5 .  CHBr .  CHBr .  CH :  C 

COOEt 

Several  other  similar  instances  are  known,  and  it  appears 
that,  though  in  the  main  the  partial  valency  theory  is  most 
useful,  in  some  cases  it  is  necessary  to  take  into  account  the 
influence  exerted  upon  the  addition  reaction  by  substituents 
near  the  double  bond. 

This  part  of  the  subject  has  been  investigated  by  Bauer,1 
who  was  able  to  substantiate  Nef  s  view 2  that  addition  reactions 
may  be  influenced  in  this  way.  Bauer  showed  that  if  we 
accumulate  phenyl,  carboxyl,  or  carbethoxyl  groups  or  bromine 
atoms  in  the  neighbourhood  of  a  double  bond,  bromine  is  not 
easily  taken  up  by  the  double  linking.  For  instance,  if  we  take 
the  general  formula — 

B          R 


k 


C 


and  make  KI  a  carboxyl  group,  bromine  will  be  added  on, 
unless  the  other  B  groups  are  bromine  atoms,  or  bromine  atoms 
with  some  methyl  groups.  Methyl  groups  alone  do  not  hinder 
the  addition.  Thus  we  get  addition  of  bromine  in  the  case 
of  acrylic  acid,  a-  and  /3-bromacrylic  acids,  crotonic  and  isocro- 
tonic  acids,  dimethylacrylic  acid,  tiglic  acid  and  trimethylacrylic 

1  Bauer,  Ber.t  1904,  37,  3488. 

2  Nef,  Annalen,  1898,  298,  208. 


262      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

acid.  No  addition  of  bromine  takes  place  in  the  cases  of  tri- 
bromacrylic  and  dibromcro tonic  acids. 

If  we  replace  EI  and  E4  by  carboxyl  groups,  addition  of 
bromine  remains  possible  as  long  as  E2  and  E3  are  not  either 
bromine  atoms  or  methyl  groups.  Thus  bromine  will  attack 
maleic,  fumaric,  mesaconic,  or  bromomaleic  acid,  but  it  will 
not  attack  the  double  bonds  of  dimethylf  umaric,  dibromofumaric, 
or  bromo-mesaconic  acid. 

If  EI  is  a  phenyl  radical,  and  the  other  three  Es  methyl 
groups,  the  compound  takes  up  a  molecule  of  bromine.  If  KI 
and  E4  are  phenyl  groups,  and  one  of  the  remaining  Es  is  a 
hydrogen  atom,  the  compound  will  react  with  bromine ;  but  if 
in  addition  to  the  two  phenyl  groups  we  introduce  two  bromine 
atoms,  the  additive  power  ceases.  Thus  while  addition  takes 
place  in  the  case  of  stilbene,  methyl-stilbene,  or  bromo-stilbene, 
it  fails  in  the  case  of  dibromostilbene. 

If  for  EI  and  E2  we  substitute  phenyl  groups,  while  the 
other  two  Es  are  hydrogen  atoms  or  alkyl  groups,  we  enter  a 
new  phase;  for  now  we  have  first  an  addition  reaction,  and 
then  a  spontaneous  loss  of  hydrobromic  acid,  leaving  us  with  a 
bromo-substituted  unsaturated  compound.  In  this  way  behave 
diphenyl-ethylene,  diphenyl-propylene,  diphenyl-methyl-pro- 
pylene ;  but  no  addition  of  bromine  takes  place  in  the  cases  of 
diphenyl-bromo-ethylene,  diphenyl-bromo-propylene,  or  tetra- 
phenyl-ethylene. 

In  a  later  paper l  Bauer  showed  that,  when  placed  near  a 
double  bond,  the  phenyl  group  had  a  certain  effect  upon  the 
addition  of  bromine,  the  carbethoxyl  group  had  more,  while 
the  nitrile  group  had  the  strongest  influence  of  the  three. 

It  was  also  found  that  the  influence  of  the  phenyl  group 
was  weakened  by  nitration,  a  nitro-group  in  the  meta-position 
having  least  effect,  and  one  in  the  ortho-position  the  most 
influence. 

Bauer  showed  further  that  the  addition  of  bromine  to  the 
double  bond  is  a  reversible  reaction,  equilibrium  being  attained 
at  different  stages  according  to  the  effect  of  the  substituents 
introduced  into  the  molecule. 

It  is  a  curious  fact  that  substituents  which  influence  the 

1  Bauer,  /.  pr.  Chem.,  1905,   II.  72,  201 ;   Bauer  and  Moser,  Ber.t  1907, 
40,  918. 


SOME    THEORIES   OF  ADDITION  REACTIONS     263 

addition  of  bromine  have  a  parallel  effect  upon  the  dissociation 
constant  of  acids,  the  effect  of  a  phenyl  group  in  the  one 
case,  for  instance,  being  less  than  that  of  a  cyanide  radicle, 
and  the  same  holding  good  in  the  case  of  the  dissociation 
constants. 

Somewhat  similar  results  have  been  obtained  by  Klages 1 
in  the  course  of  his  researches  on  the  reduction  of  styrolene 
derivatives. 

It  will  be  noticed  that  in  all  the  foregoing  views  the 
question  is  treated  purely  from  a  static  standpoint ;  the  double 
bond  is  regarded  more  or  less  as  a  kind  of  hook  which  can 
fix  itself  upon  any  atom  wandering  in  the  neighbourhood. 
Stewart's  view  differs  from  the  others  in  that  it  concerns  itself 
more  with  the  dynamics  of  intramolecular  change  than  with 
the  purely  static  side. 

In  the  first  place,  we  may  give  a  brief  account  of  the 
chemical  evidence  upon  which  this  view  is  based.  Stewart 2 
first  showed  that  the  reactive  power  of  the  carbonyl  group  in 
acetoacetic  ester  greatly  exceeded  that  of  the  carbonyl  radicle 
in  acetone.  Later3  he  proved  that  the  carbonyl  radicle  of 
acetone  dicarboxylic  ester  was  even  more  reactive  than  that  of 
acetoacetic  ester.  On  the  other  hand,  the  carbonyl  groups  in 
Isevulinic  ester  and  in  acetonylacetone  were  much  less  reactive 
than  those  of  acetone.  Acetylacetone  proved  to  be  more  re- 
active than  either.  Pinacoline  was  the  least  reactive  of  all 
the  ketones  examined. 

Taking  acetone  as  the  highest  substance  in  the  "slight 
reactivity"  class  we  can  arrange  the  two  sets  of  compounds 
thus — 

Low  Reactivity.  High  Reactivity. 

4  I  Acetone  ^  i  (Acetone) 

|     Lsevulinic  ester  §     Acetoacetic  ester 

g     Acetonylacetone  b     Acetylacetone 

p  v  Pinacoline  «  v  Acetone  dicarboxylic  ester 

And  when  we  examine  the  "  reactive "  group  we  find  that  all 
the  substances  which  it  contains  are  tautomeric  bodies,  which 
are  capable  of  yielding  sodium  derivatives,  and  whose  methylene 
hydrogen  atoms  are  easily  replaced  by  halogens.  In  other 

1  Klages,  Ber.,  1903,  36,  3584;  1904,  37,  1721,  2301. 

2  Stewart,  Trans.  Chem.  Soc.,  1905,  87,  185. 

3  Stewart,  Proc.  Chem.  Soc.,  1905,  21,  78. 


264      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

words,  not  only  is  the  carbonyl  group  in  each  of  them  very 
reactive,  but  the  hydrogen  atoms  of  the  neighbouring  methylene 
group  share  this  activity.  On  the  other  hand,  none  of  the 
"  weakly  reactive "  group  are  strongly  tautomeric,  and  their 
hydrogen  atoms  are  not  acidic  to  any  great  extent. 

Now,  in  the  case  of  the  substance  acetoacetic  ester,  for 
instance,  it  is  obvious  that  the  hydrogen  atoms  in  the  methylene 
group  must  be  very  closely  related  to  the  oxygen  atom  of  the 
carbonyl  group ;  for  if  they  were  not,  it  is  difficult  to  understand 
how  the  sodium  derivative  of  such  substances  is  derived  from 
the  hydroxylic  form  of  the  compound.  Without  actually  sup- 
posing that  the  hydrogen  atom  wanders  freely  between  the 
carbon  and  oxygen  atoms,  as  in  the  Laar  hypothesis,  it  must  be 
admitted  that  the  oxygen  atom  exercises  some  influence  upon 
the  hydrogen  atone,  and  vice  versa.  This  influence  will  be  most 
strongly  marked  in  the  case  of  acetone  dicarboxylic  ester,  but  it 
will  be  perceptible  even  in  simple  ketones. 

Let  us  next  consider  the  effect  which  this  influence  will 
have  upon  the  various  atoms  in  the  molecule.  If  we  take  the 
case  of  the  grouping — 

(1)    (2) 
R— C— CH— X 

O     H 

(3) 

it  is  obvious  that  the  affinity  of  the  carbon  atom  (1)  is  occupied 
in  part  by  the  group  K,  part  by  the  carbon  atom  (2),  and  the 
remainder  is  devoted  to  saturating  the  affinity  of  the  oxygen 
atom.  Similarly,  the  affinity  of  the  carbon  atom  (2)  is  distri- 
buted between  the  group  X,  the  carbon  atom  (1),  and  the 
hydrogen  atoms.  But  since  there  is  some  relation  between  the 
oxygen  atom  and  the  hydrogen  atom  (3),  some  of  the  affinity 
of  these  two  atoms  must  be  used  up  in  mutual  attraction,  and 
the  more  tautomeric  the  compound  is,  the  more  affinity  will 
thus  be  employed.* 

Eegarded  in  this  way,  the  molecule  would  represent  a  closed 
system,  the  affinities  of  whose  atoms  are  mutually  saturated. 

*  Tautomeric  is  perhaps  not  the  correct  word;  what  is  meant  is  that  the 
affinity- exchange  between  the  two  atoms  will  be  greatest  in  the  case  where  the 
methylene  hydrogen  atoms  are  most  strongly  acidic. 


SOME    THEORIES   OF  ADDITION  REACTIONS      265 

But  if  we  take  into  account  the  intramolecular  motions  of  atoms, 
the  case  at  once  assumes  a  different  aspect.  It  is  obvious  that 
the  influence  exerted  by  the  hydrogen  atom  (3)  upon  the 
oxygen  atom  will  not  be  constant,  but  will  vary  according  to 
the  distance  between  these  atoms.  If  we  assume,  as  is  usually 
done,  that  the  atoms  within  a  molecule  vibrate  in  closed  paths 
about  relatively  fixed  centres,  it  is  evident  that  the  hydrogen 
atom  will  be  now  approaching,  now  retreating  from  the  oxygen 
atom.  Every  approach  will  ent:til  a  rearrangement  of  the 
affinity  of  the  two  atoms,  and  another  rearrangement  of  affinity 
will  take  place  during  their  retreat  from  each  other.  Stewart 
considers  that  this  rearrangement  of  affinity  of  these  two  atoms 
is  the  cause  of  their  chemical  activity.  In  a  closed  or  stable 
system  of  forces  the  introduction  of  a  new  element  is  difficult ; 
but  if  a  system,  be  in  a  state  of  unstable  or  continually  varying 
equilibrium  it  is  more  readily  amenable  to  change. 

Now,  in  tautomeric  compounds,  since  the  oxygen  and 
hydrogen  atoms  exert  great  influence  upon  each  other,  this 
redistribution  of  affinity  will  be  much  more  strongly  marked 
than  in  the  case  of  substances  like  acetone,  whose  hydrogen 
atoms  are  only  very  weakly  acidic ;  and  when  we  replace  the 
hydrogen  atoms  of  acetone  by  methyl  groups  we  shall  still 
further  lessen  the  possible  influence  upon  the  oxygen  atom, 
which  serves  to  make  clear  the  very  low  reactivity  of  the 
carbonyl  group  in  pinacoline.  Support  is  lent  to  Stewart's 
views  by  the  evidence  of  the  absorption  spectra  of  the 
above-mentioned  ketonic  compounds  which  were  examined  by 
Stewart  and  Baly.1 

We  must  now  turn  to  the  question  of  the  a-diketones  and 
quinones,  which  also  contain  very  reactive  carbonyl  groups. 
When  the  reactivity  of  the  carbonyl  group  in  pyruvic  ester 
was  determined  by  Stewart's  method,2  it  was  found  to  be 
more  active  than  any  of  those  previously  dealt  with.  Now, 
in  this  case,  we  can  hardly  suppose  that  there  is  any  great 
attraction  between  the  hydrogen  atoms  of  the  methyl  radicle 
and  the  oxygen  of  the  carbonyl  group :  the  chemical  behaviour 
of  the  substance  gives  us  no  right  to  draw  any  such 

1  Stewart  and  Baly,  Trans.  Chem.  Soc.,  1906,  89,  489 ;  of.  Stewart  and  Baly, 
Trans.  Chem.  Soc.,  1906,  89,  618. 

2  Stewart,  Tran*.  Chem.  Soc.,  1905,  87,  185. 


266      RECENT  ADVANCES  JN   ORGANIC  CHEMISTRY 

conclusion  ;  and  the  spectroscopic  evidence,  as  far  as  it  can  be 
considered  relevant  in  a  purely  chemical  question,  tends  to 
disprove  the  existence  of  any  such  mutual  influence.  We  are 
therefore  forced  to  a  new  point  of  view. 

.  If  we  assume  that  instead  of  a  mutual  attraction  between 
the  oxygen  and  hydrogen  atoms  we  have  a  similar  attraction 
between  the  oxygen  atoms  of  the  two  carbonyl  groups  in 
pyruvic  ester,  we  should  be  able  to  explain  how  in  that  sub- 
stance a  redistribution  of  affinity  is  going  on  which  to  some 
extent  will  resemble  that  in  acetoacetic  ester.  But  we  may 
go  even  further  in  this  case,  and  assume  that  as  an  extreme 
form  of  the  intramolecular  vibration  we  have  almost  a  rearrange- 
ment of  bonds  such  as  is  expressed  in  the  following  formula  :  — 

CH3—  C—  C—  OEt  CH3—  C=C—  OEt 

II      II  II 

0     0  0—0 

In  pyruvic  ester  it  is  doubtful  whether  this  change  ever 
takes  place  ;  we  have  only  spectroscopic  evidence  in  support  of 
it,  not  chemical.  But  there  is  a  parallel  case  in  which  we  can 
bring  actual  chemical  evidence  in  support  of  this  attraction 
between  the  two  oxygen  atoms.  Wills  tatter  and  Miiller,1  by 
oxidizing  catechol  with  silver  oxide,  have  succeeded  in  isolating 
ortho-benzoquinone  in  two  isomeric  forms,  to  one  of  which  they 
ascribe  the  dicarbonyl  formula  (I.),  while  the  other  they  suppose 
to  have  the  structure  (II.)  — 

CH  CH 

^    \  /    \ 

HC  C=0  HC  C—  0 

II  I  II      I 

HC  0=0  HC  C—  O 

v          v 


It  is  well  known  that  the  para-positions  of  the  benzene 
ring  are  closely  related  to  each  other,  more  closely  than 
the  ordinary  structural  formulae  indicate;  and  in  the  case  of 
the  quinones,  this  connection  is  very  strongly  marked  in  the 

1  Willstatter  and  Muller,  Ber.,  1908,  41,  2580, 


SOME    THEORIES    OF  ADDITION  REACTIONS      267 

reactions  of  the  two  carbonyl  radicles.  Now,  quinone  itself  is 
a  tautomeric  body  which  reacts  as  if  it  had  either  of  the  two 
structures  shown  below — 

0 

II 

C  C 

/\  /\\ 

HC         CH  HC    0    CH 

II  II  II      | 

HC          CH  HC    O 

\/  \J> 

C  C 

II 

0 

(I.)  (II.) 

Hence  it  is  obvious  that  in  this  case  we  actually  have  a  change 
taking  place  which  converts  the  compound  (I.)  into  the  com- 
pound (II.),  and  vice  versa.  This  change  is  perfectly  analogous 
to  that  which  we  have  already  written  down  in  the  case  of 
pyruvic  ester,  though  in  that  compound  we  had  no  chemical 
evidence  for  the  two  formulse  such  as  we  have  in  the  case  of 
quinone.  The  conversion  of  the  quinone  (I.)  into  the  quinone 
(II.)  and  its  reverse  would  produce  that  redistribution  of 
affinity  upon  the  oxygen  atoms  which  we  have  postulated  as 
the  cause  of  the  chemical  activity  in  carbonyl  groups  ;  and  the 
vibrations  of  the  benzene  ring  itself  suffice  to  explain  why  this 
conversion  takes  place,  for  in  one  phase  we  should  expect  to 
find  the  carbonyl  groups  near  to  each  other,  while  in  another 
phase  they  may  be  far  apart,  and  therefore  unable  to  exert 
much  influence  upon  each  other. 

Analogous  ideas  have  been  applied  by  Baly  l  to  the  case 
of  the  colour  of  some  nitrogen  compounds,  but  as  we  are 
dealing  purely  with  the  chemical  side  of  the  question  here  we 
need  not  enter  into  any  discussion  of  this  physical  property. 

Forster  2  suggests  that  we  might  regard  the  oxygen  atom 
as  changing  its  valency  in  these  cases,  so  that  the  extreme 

1  Baly,   Edwards  and  Stewart,    Trans.  Chem.  Soc.,  1906,  89,  514;  Baly, 
Marsden  and  Stewart,  ibid.,  966. 

2  Forster,  private  communication  to  the  author. 


268      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

phase  of  the  vibration  in  the   case  of  camphor-quinone,   for 
example,  might  be  written  thus  — 

C=0 

C8H14 


and  this  view  appears  to  have  much  to  recommend  it. 

By  means  of  the  foregoing  hypothesis,  then,  we  are  enabled 
to  give  some  explanation  of  a  series  of  apparently  quite  dis- 
connected facts:  the  reactivity  of  aliphatic  ketones  and  diketones, 
the  tautomeric  power  of  these  substances,  the  sensitiveness  of 
the  hydrogen  atoms  in  the  grouping  —  CO  .  CH2  .  CO  —  ,  the 
extreme  chemical  reactivity  of  the  quinones  ;  and  by  a  slight 
extension  of  the  hypothesis  we  could  explain  also  the  ease 
with  which  the  a-hydrogen  atoms  of  acids  are  replaced  by 
halogens. 

The  foregoing  brief  account  of  the  various  theories  of 
addition  reactions  only  serves  to  throw  into  relief  the  insuffi- 
ciency of  our  present  views  on  this  subject.  On  the  one 
hand,  we  have  ideas  which  are  so  vague  as  to  convey  very 
little  meaning,  while  on  the  other  we  have  mechanical  hypo- 
theses which  are  too  inelastic  to  cover  anything  but  a  very 
narrow  field.  The  most  useful  of  all  the  suggestions  hitherto 
put  forward,  Thiele's  partial  valencies,  deals  rather  with  the 
facts  themselves  than  with  any  explanation  of  them,  and  takes 
little  account  of  subtle  differences  in  reactivity.  The  field  is 
tempting  to  the  theorist,  however,  and  perhaps  before  long  we 
may  have  some  view  which  will  combine  the  advantages  of  all 
the  present  hypotheses  without  their  drawbacks. 


CHAPTER  XIII 

UNSATURATION 

WHEN  we  examine  the  matter  closely,  we  find  that  the  founda- 
tions of  theoretical  organic  chemistry  are  a  series  of  labels  by 
means  of  which  we  endeavour  to  conceal  our  ignorance  of  the 
fundamental  phenomena  of  the  subject.  Of  these  labels, 
none  is  used  more  indefinitely  and  at  random  than  the  word 
"  Unsaturation."  It  seems  not  without  some  interest,  there- 
fore, to  examine  the  various  phenomena  which  are  usually 
ascribed  to  the  presence  of  this  property,  and  to  see  how  far 
we  can  attain  to  some  clear  idea  of  what  we  mean  by  the 
word. 

In  the  first  place,  let  us  ask  ourselves  what  we  mean  by 
an  unsaturated  compound.  The  picture  which  is  formed  in 
our  mind  by  these  words  usually  represents  two  molecules 
uniting  together,  and  one  of  these  we  are  accustomed  to  call 
an  unsaturated  substance.  But  before  going  further  we  are 
faced  by  a  difficulty,  for  there  seems  no  reason  why  we  should 
consider  one  of  the  two  molecules  unsaturated  and  the  other 
saturated.  For  example,  if  a  molecule  of  bromine  unites 
with  a  molecule  of  ethylene,  we  call  ethylene  an  unsaturated 
hydrocarbon,  but  we  do  not  regard  the  bromine  molecule  as 
unsaturated  in  the  same  sense.  If  we  examine  the  matter 
more  closely,  however,  the  difference  between  the  two  cases 
becomes  clear.  When  ethylene  takes  up  an  atom  of  bromine 
the  ethylene  molecule  is  not  completely  disrupted ;  part  of  it 
remains  as  it  was,  for  the  two  carbon  atoms  are  still  united, 
and  each  bears  the  same  number  of  hydrogen  atoms  as  before. 
With  the  bromine  molecule,  however,  no  trace  of  the  original 
structure  remains.  Evidently  our  idea  of  an  unsaturated  com- 
pound must  be  extended ;  it  is  no  longer  sufficient  to  say  that 
it  is  "  a  molecule  capable  of  uniting  with  another  molecule " ; 
but  we  must  add,  "without  a  disruption  of  its  original 


270      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

structure."  This  definition  covers  practically  every  case  which 
has  any  claims  to  be  considered ;  and  we  may  therefore  adopt 
it  and  proceed  to  inquire  if  we  can  distinguish  further  between 
the  various  classes  of  substances  which  come  within  the 
definition. 

The  simplest  type  of  an  unsaturated  compound  with  which 
we  can  deal  is  a  component  of  a  double  salt.  Here  the  amount 
of  unsaturation  is  very  slight,  for  we  may  decompose  the 
saturated  body  (double  salt)  into  its  components  again  by  a 
mere  lowering  of  temperature. 

The  second  class  of  unsaturated  compounds  includes  those 
in  which  the  addition  of  new  atoms  takes  place  at  one  atom 
only,  as,  for  example,  trimethylamine,  dimethyl-sulphide, 
dimethyl-pyrone,  etc.  In  this  case  the  least  possible  change 
in  the  general  structure  of  the  molecule  takes  place  during  the 
addition  reaction. 

The  third  class  of  unsaturated  compounds  contains  those 
bodies  which  are  capable  of  uniting  with  two  atoms,  but  in 
which  addition  takes  place  at  two  adjacent  atoms.  The 
ethylene  series,  the  ketones,  and  the  nitriles  are  instances  of 
this  type. 

There  is  another  class  of  bodies  which,  while  resembling  the 
last-mentioned  one,  in  so  far  as  their  capability  of  adding  on 
only  one  pair  of  atoms  is  concerned,  differs  from  it  in  the 
manner  of  addition  ;  for,  instead  of  the  two  new  atoms  attaching 
themselves  to  two  adjacent  atoms,  as  in  the  ethylene  class,  in 
this  new  series  they  attach  themselves  to  non-adjacent  carbon 
atoms.  The  polymethylenes  are  a  case  in  point. 

Finally,  we  come  to  the  acetylene  class,  in  which  we  are 
able  to  unite  four  new  atoms  to  two  of  the  carbon  atoms  of  the 
unsaturated  compound. 

Thus  we  have  divided  unsaturated  bodies  into  the  following 
five  classes : — 

1.  Components  of  molecular  compounds. 

2.  Compounds   of  mono-valent    iodine,   divalent    sulphur, 

selenium,   tellurium,  oxygen,  etc.,  trivalent   nitrogen, 
phosphorus,  antimony,  etc. 

3.  Compounds  containing  groups  like  C :  C  ,  C  :  N ,  C  :  0. 

4.  Cyclic  compounds. 

5.  The  acetylenes. 


UNSA  TURA  TION  27 1 

Of  course,  it  is  quite  easy  to  multiply  the  possibilities  by 
combining  in  one  molecule  representatives  of  each  class,  as  in 
the  case  of  mesityl  oxide,  for  instance ;  but  if  we  reduce  the 
question  to  its  simplest  form,  the  above  series  will  serve  as  a 
mode  of  classification. 

Before  entering  into  a  consideration  of  these  classes,  how- 
ever, we  must  deal  with  two  other  points  which  arise.  What 
we  call  an  unsaturated  substance  may  be  unsaturated  with 
regard  to  one  agent,  and  quite  saturated  towards  another.1  For 
instance,  if  we  take  the  substances  in  Class  3,  though  all  of 
them  are  unsaturated  with  respect  to  nascent  hydrogen,  they 
differ  in  their  behaviour  towards  bromine,  ammonia,  or  water. 
Again,  it  is  sometimes  found  that  a  compound  may  behave  as 
a  saturated  or  an  unsaturated  substance  according  to  the  con- 
ditions under  which  reactions  are  carried  out.  For  example,  in 
sunlight  benzene  forms  addition  products  much  more  easily 
than  in  the  dark.  Thus  there  are  fine  differences  for  which  we 
have  no  corresponding  technical  terms. 

It  would  occupy  too  much  space  were  we  to  enter  into  any 
detailed  examination  of  the  differences  in  physical  properties 
between  saturated  substances  and  the  unsaturated  bodies  from 
which  they  have  been  prepared.  There  is  hardly  a  single 
physical  property  which  remains  common  to  the  two  groups. 
Melting-point,  boiling-point,  refractive  index,  optical  rotatory 
power,  absorption  spectrum,  magnetic  rotation,  crystalline  form, 
electrical  conductivity,  and  a  host  of  other  properties  are  all 
changed  by  the  addition  of  as  many  atoms  as  the  unsaturation 
requires. 

The  chemical  effects  of  unsaturation  are  hardly  less  marked. 
Leaving  out  of  consideration  the  chemical  difference  implied  in 
the  fact  that  the  unsaturated  compound  is  capable  of  adding  on 
more  atoms,  while  the  saturated  one  is  not,  there  are  many 
other  differences  which  the  presence  or  absence  of  unsaturation 
in.  the  molecule  brings  into  view.  For  example,  if  we  take  a 
saturated  aliphatic  acid  and  the  corresponding  unsaturated 
substance  in  which  the  double  bond  lies  next  the  carboxyl 
group,  the  saturated  acid  will  esterify  with  much  greater  ease 
than  the  unsaturated  one.2  Again,  unsaturation  may  call  into 

1  See  Vorlander,  Annalen,  1902,  320,  66. 

2  Sudborough  and  Koberts,  Trans.  Chem.  Soc.,  1905,  87,  1840 ;  Sudborough 
and  ThomaB,  ibid.t  1907,  91,  1033. 


272      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

being  a  peculiar  type  of  isomerism,  of  which  the  best  example 
is  found  in  the  case  of  maleic  and  fumaric  acids.  Further,  in 
the  case  of  the  acetylene  series,  the  presence  of  unsaturation  so 
alters  the  chemical  characters  of  the  hydrogen  atoms  that  they 
become  replaceable  by  metallic  atoms ;  while,  if  we  accumulate 
acetylenic  linkages  in  a  compound,  it  may  become  so  unstable 
as  to  decompose  with  explosive  violence.  These  few  examples 
will  suffice  to  illustrate  the  very  varied  influences  exerted  on 
the  properties  of  compounds  by  unsaturation. 

We  may  now  turn  to  the  question  of  the  relative  stability 
of  various  unsaturated  compounds.  In  the  first  place,  it  is 
obvious  that  the  amount  of  energy  which  is  used  up  in  satu- 
rating the  component  of  a  double  salt  cannot  be  very  great ;  for 
if  it  were  so,  the  double  salt  would  not  be  decomposed  again 
into  its  components  with  the  ease  which  is  found  in  practice. 
In  the  second  class,  we  obtain  saturated  compounds  by  calling 
into  existence  some  latent  affinities  on  the  sulphur  or  nitro- 
gen atoms.  Now,  these  new  salts — sulphoniurn,  ammonium, 
phosphonium,  or  whatever  they  be — can,  in  many  cases,  be 
broken  down  into  the  unsaturated  substance  again  by  very 
simple  means.  For  instance,  merely  by  heating  the  quaternary 
ammonium  salts  we  can  obtain  the  amido-compounds  from 
which  we  started.  Thus,  though  we  have  here  a  set  of  sub- 
stances more  stable  than  the  double  salts,  still  the  increase  in 
stability  is  not  very  great.  When  we  come  to  the  groups  3,  4, 
and  5,  the  change  from  the  saturated  to  the  unsaturated  body 
can  only  be  brought  about  by  chemical  means,  so  that  in  their 
case  we  have  passed  into  a  new  stage  of  the  question. 

There  is  another  way  in  which  we  can  look  at  the  matter, 
and,  for  the  sake  of  simplicity,  we  may  confine  our  investiga- 
tion in  the  rest  of  this  chapter  to  the  cases  of  the  carbon 
compounds.  If  we  take  an  ethylene  derivative  and  compare  it 
with  the  isomeric  polymethylene,  we  find  that  the  former  is 
much  more  readily  attacked  by  reagents  than  the  latter;  in 
other  words,  the  ethylene  type  is  more  unsaturated  than  the 
polymethylene.  Thus,  while  ethylene  compounds  are  almost 
instantaneously  oxidized  by  permanganate,  the  polymethy- 
lenes  are  not  so  rapidly  destroyed.  The  acetylene  series  is 
even  more  sensitive  to  oxidizing  agents  than  the  ethylenes. 

A  somewhat  interesting  point  arises  when  we  combine  in 


UNSA  TURA  TION  273 

one  molecule  two  different  types  of  unsaturation,  and  then 
endeavour  to  find  out  which  of  them  is  the  more  readily  satu- 
rated. For  example,  if  we  take  the  case  of  mesityl  oxide,  we 
have  in  one  molecule  the  double  bond  between  two  carbon 
atoms,  and  the  other  double  bond  between  a  carbon  and  an 
oxygen  atom  — 

(CH3)2C 
II 
CH 

CH3—  C 

II 
0 

These  two  double  bonds  are  of  different  types,  and  hence  we 
should  expect  to  find  some  differences  between  their  chemical 
activities.  In  the  first  place,  of  course,  we  find  that  the  one 
bond  will  react  with  halogen  acids,  which  do  not  attack  the 
carbonyl  group.  But  if  we  leave  out  of  account  such  differ- 
ences and  confine  ourselves  to  the  action  of  those  reagents 
which  are  capable  of  reacting  with  both  linkages,  the  results 
are  sufficiently  striking.  If  we  reduce  mesityl  oxide  by  means 
of  weak  alkaline  reagents,  such  as  sodium  amalgam  or  alumi- 
nium amalgam,  the  carbonyl  group  remains  intact,  while  the 
double  bond  is  opened  up.  Two  molecules  of  the  ketone  unite 
together  to  form  a  saturated  diketone  — 

(CH3)2C.CH2.CO.CH3 
(CH3)2C.CH2.CO.CH3    • 

(In  the  case  of  aliphatic  ketones  this  diketone  further  condenses 
to  a  cyclic  compound,  in  this  instance  desoxy-mesityl  oxide  _ 

(CH3)2C  --  CH2\ 


(CH3)2C-         -C-CO  .  CH3 

while  in  the  aromatic  series  the  reaction  may  be  stopped  at  the 
first  stage.) 

When  we  use,  as  a  reducing  agent,  sodium  in  aqueous  ether, 
the  reaction  takes  quite  a  different  course,  for  here   both  the 

T 


274      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

carbonyl  and  the  ethylene  linkages  are  attacked  simultaneously, 
giving  the  saturated  alcohol  — 

(CH3)2CH  .  CH2  .  CH(OH)  .  CH3 

No  method  has  yet  been  discovered  by  which  we  can  reduce 
the  carbonyl  group  of  mesityl  oxide  without  destroying  the 
ethylene  linkage  as  well. 

But  if  we  take  the  case  of  another  ketone,  such  as  — 

CH2:CH.CH2.CO.CH3 

we  shall  find  no  difficulty  whatever  in  reducing  it  with  sodium 
in  alcohol  or  aqueous  ether  to  the  unsaturated  alcohol  — 

CH2  :  CH  .  CH2  .  CH(OH)  .  CH3 

If  we  examine  the  structures  of  the  two  substances  we  find 
that  in  the  case  of  mesityl  oxide  we  have  a  conjugated  double 
bond,  while  in  that  of  the  second  ketone  we  have  two  unconju- 
gated  linkages  ;  thus  in  the  case  of  mesityl  oxide  we  cannot 
attack  one  bond  without  tampering  with  the  other,  while  in 
the  second  case  we  can  reduce  either  separately.  If  we  examine 
the  progress  of  the  reaction  which  we  should  expect  from  Thiele's 
hypothesis  in  the  case  of  mesityl  oxide,  we  find  that  in  the  first 
place,  hydrogen  adds  on  to  the  two  end  partial  valencies,  as 
shown  below  — 

(CH3)2C  ......  H  (CH3)2CH 

II  I 

H.C,  CH 

I  ) 


0  CH3  .  \j 

II  I 

0  ......  H  OH 

But  this  new  body  is  merely  the  enolic  form  of  the  ketone  — 
(CH3)2CH.CH2.CO.CH3 

into  which  it  will  rearrange  itself  at  once.  Thus  it  is  easy  to 
understand  why  the  carbonyl  group  is  never  attacked  first 
when  it  is  conjugated  with  another  double  bond  of  a  different 
nature. 

Again,  ammonia  is  an  agent  which  is  capable  of  acting  both 
upon  carbonyl  groups  and  on  ethylenic  linkages,  but  if  we  allow 
it  to  react  with  mesityl  oxide  it  attacks  only  the  double  bond 


UNSA  TURA  TION  27  5 

between  the  carbon  atoms  and  leaves  intact  the  carbonyl 
radicle — 

(CH3)2C  (CH3)2C.NH2 

II         +  NH3  =  | 

CH3.CO.CH  CH3.CO.CH2 

Mesityl  oxide.  Diacetonamine. 

The  matter  becomes  a  little  clearer  when  we  consider  the 
action  of  hydroxylamine  upon  mesityl  oxide.1  If  the  action  is 
allowed  to  take  place  in  a  methyl  alcoholic  solution  in  presence 
of  sodium  methylate,  the  chief  product  is  the  substance  formed 
by  the  addition  of  hydroxylamine  to  the  double  bond — 

(CH3)2C .  CH2 .  CO  .  CH3 
NH.OH 

But  if,  on  the  other  hand,  we  take  hydroxylamine  hydrochloride 
and  after  exactly  neutralizing  it  with  sodium  carbonate  allow  it 
to  act  upon  an  alcoholic  solution  of  mesityl  oxide,  we  get  the 
usual  carbonyl  group  reaction,  and  mesityl  oxime  is  formed — 

(CH3)2C :  CH .  C(NOH) .  CH3 

Thus  in  alkaline,  solution  the  ethylenic  bond  is  stimulated  into 
activity,  while  in  neutral  solution  the  carbonyl  radicle  appears 
the  more  reactive  of  the  two. 

The  influence  of  the  conjugated  double  bond  makes  itself 
felt  also  in  the  cases  of  propenyl  and  allyl  methyl  ketones. 
Blaise 2  has  examined  these  two  isomeric  substances,  and  finds 
that  when  treated  with  one  molecule  of  hydroxylamine  in  a 
neutral  solution  they  are  both  converted  into  oximes — 

CH3 .  CH :  CH .  CO  .  CH3  ->  CH3 .  CH :  CH .  C(NOH) .  CH3 
CH2 :  CH .  CH2 ,  CO  .  CH3  ->  CH2 :  CH .  CH2 .  C(JSTOH) .  CH3 

But  if  we  treat  them  with  two  molecules  of  hydroxylamine  the 
results  are  different ;  allyl  methyl  ketone  reacts  as  in  the  last 
case,  giving  the  oxime  shown  above,  while  propenyl  methyl 

1  Harries  and  Lellmann,  Ser.t  1897,  30,  230,  2726;  Harries  and  Jablonski, 
ibid.,  1898,  31,  1371;  Harries,  Annalen,  1904,  330,  191. 

2  Blaise,  Bull  soc.  chim.,  1905,  III.  33,  42. 


276      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

ketone  reacts  with  two  molecules  of  hydroxylamine  to  give  the 
hydroxylamineoxime  derivative  shown  below  — 


I 
CH.NH.OH 


CH3.C:  NOH 

Thus  the  conjugation  of  the  ethylene  and  carbonyl  bonds 
increases  the  activity  of  the  ethylenic  linkage  in  this  case  also. 
Blaise  showed  that  exactly  similar  results  were  obtained  with 
semicarbazide,  the  allyl  ketone  forming  a  semicarbazone,  while 
the  propenyl  ketone,  in  virtue  of  its  conjugated  bonds,  took  up 
a  second  molecule  of  semicarbazide  to  form  a  semicarbazide- 
semicarbazone. 

Posner 1  has  studied  the  matter  very  fully  in  order  to  find 
what  effect  various  groups  exert  when  placed  near  the 
ethylenic  double  bond.  In  the  first  place,  he  proved  that  the 
ethylenic  linkage  alone  was  capable  of  taking  up  hydroxyl- 
amine and  mercaptans,  so  that  this  addition  capacity  does  not 
depend  entirely  upon  the  proximity  to  the  carbonyl  group. 
When  unsaturated  acids  were  used,  he  found  that  the  activity 
of  the  double  bond  was  weakened  if  the  carboxyl  group  was 
placed  in  its  vicinity.  Thus  neither  maleic  nor  fumaric  acid 
can  be  induced  to  combine  with  hydroxylamine  except  to 
form  the  usual  salts;  phenyl-isocrotonic  acid,  on  the  other 
hand,  in  which  the  ethylene  linkage  is  not  conjugated  with  the 
double  bond  of  a  carboxyl  group,  takes  up  a  hydroxylamine 
molecule  with  special  ease,  a/3 -unsaturated  monocarboxylic 
acids  give  with  hydroxylamine  a-oximino-acids,  whilst  a/3-un- 
saturated  ketones  form  /3-hydroxylamine  derivatives. 

Thus  we  cannot  say  definitely  that  the  ethylenic  linkage  is 
more  or  less  active  than  the  carbonyl  bond ;  for  the  matter  is 
influenced  in  different  ways  by  the  reagent  employed,  the 
solvent  used  and  the  relative  position  of  the  two  double  bonds 
in  the  molecule.  In  other  words,  "  unsaturation "  is  not  a 
definite,  measureable  thing  which  we  can  predict  in  any  case 
from  the  behaviour  of  the  "  unsaturated  "  substance  in  other 

1  Posner,  Ber.,  1901,  34,  1395;  1902,  35,  799;  1903,  36,  4305;  1905,  38,  646; 
190G,  39,  3515  ;  1907,  40,  218  ;  Posner  and  Oppermann,  ibid.,  1906,  39,  3705. 


UNSA  TURATION  277 

circumstances  ;  it  is  rather  something  kinetic,  something  which 
is  extremely  sensitive  to  external  forces,  and  which  in  its  turn 
can  play  a  part  in  influencing  the  chemical  action  of  groups 
which  it  does  not  apparently  affect  directly. 

As  an  example  of  this  latter  property  we  may  quote  the  case 
of  the  Vorlander  Eule.1  Vorlander  has  pointed  out  that  we  can 
consider  both  acids  and  alcohols  as  derived  from  water  by 
substitution.  In  the  case  of  acetic  acid  we  substitute  an  acetyl 
group  for  one  of  the  hydrogen  atoms  of  water,  while  ethyl 
alcohol  is  formed  from  water  by  the  substitution  of  an  ethyl 
group  for  a  hydrogen  atom. 

H  CH3.CH2  CH3.CO 

O  0  O 

/    ^    /        / 

When  we  examine  the  chemical  behaviour  of  the  hydrogen 
atom  in  each  case,  we  find  that  in  the  acids  it  has  a  much  greater 
activity  than  in  the  alcohols.  The  origin  of  this  difference 
obviously  lies  in  the  difference  between  the  acyl  and  alkyl 
groups  to  which  the  hydroxyl  radicle  is  united.  The  question 
is  commonly  dealt  with  by  labelling  the  acyl  group  "  electro- 
negative," and  treating  the  label  as  an  explanation.  But,  as 
Vorlander  pointed  out,  this  case  is  only  one  example  of  a  general 
rule.  If  we  represent  non-metallic  elements  by  E,  and  write 
down  the  following  series  : — 

1234 

H.E.E:E 

123 

H.E:E 

12345 

H.E.E.E-.E 

we  shall  find  that  the  hydrogen  atom  in  the  first  line  has  a 
greater  reactivity  than  those  in  the  second  and  third  lines  ;  in 
the  first  case  the  double  bond  between  two  E  atoms  lies  in  the 
3  :  4  position  to  the  labile  hydrogen  atom,  while,  where  the 
double  bonds  are  in  the  2:3  or  4 :  5  positions  the  hydrogen 
atom  is  not  specially  active.  For  example,  the  labile  hydrogen 
atoms  in  oximes,  acids,  phenols,  diazo-compounds,  and  sulphuric 
1  Vorlander,  Ber.,  1901,  34,  1633. 


278      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

acids  are  all  situated  as  in  the  first  type  with  respect  to  the 
double  bond — 

4321  4321 

E.CHrK.O.H  OcC.O.H 

I 
B 

4322  4321 

R— N:N.O.H  0:S.O.H 


CH-CH 

C— 0— H 

y 

CH— CH 

4 

In  acetoacetic  ester  and  nitre-methane  the  hydrogen  atoms 
are  doubly  influenced — 

0(4)  4  0 

II  II      2      1 

CH3 .  0(3)  3  N— 0— H 

I  II 

H— C H  4  CH2 

I  (2)   (1) 
EtO— 0(3) 

0(4) 

Further,  when  an  acid  or  a  ketone  is  brominated,  the 
halogen  atom  enters  the  nucleus  in  the  position  required  by 
this  rule,  i.e.  it  replaces  the  hydrogen  atom  in  the  o -position  to 
the  carbonyl  group — 

1234  1234 

Br .  CH  .  C  :  0  Br .  CH  .  C  :  0 


E      OH  R      R 

There  seems  to  be  another  influence  at  work  in  the  case 
of  acidic  hydrogen  atoms;  and  as  the  matter  appears  to  have 
escaped  notice  hitherto,  it  may  be  well  to  call  attention  to  it 
in  this  connection.1  An  examination  of  the  formulae  of  most 
substances  which  are  capable  of  yielding  metallic  derivatives 

1  Smiles,  Trans.  Chem.  Soc.,  1900,  77,  160. 


UNSA  TURA  TION     •  ;  279 

will  show  that  the  atom  to  which  the  labile  hydrogen  is 
attached  is  capable  of  exerting  a  valency  higher  than  that 
which  it  exhibits  in  the  acidic  compound.  For  example,  in 
the  following  substances  the  oxygen  and  sulphur  atoms  are 
divalent,  while  both  oxygen  and  sulphur  are  capable  of  acting 
as  quadrivalent  elements;  carbon  in  acetylene  acts  as  a 
divalent  atom,  though  its  maximum  valency  is  four;  the 
nitrogen  atoms  shown  below  are  trivalent,  but  nitrogen  can 
act  as  a  pentad ;  iodine  can  act  either  as  a  mono-  or  a  trivalent 
element.  The  formulae  are  written  with  lines  to  show  the 
extra  valencies. 

H-I/ 


H-C— C— 


H  H— O— CH3  H— S— CH3 

I 

CH=CH 
H— NH— CO .  CH3  H— N 


It  will  be  seen  that  this  is  of  more  general  application  than 
the  Vorfander  Kule,  for  it  holds  in  the  case  of  substances  such 
as  ethylates,  whose  formation  takes  place  though  there  is  no 
double  bond  in  the  molecule  such  as  is  required  by  Vorlander's 
view. 

We  must  now  turn  to  another  point  of  view.  Hitherto  we 
have  regarded  unsaturation  from  the  standpoint  of  addition 
reactions,  but  we  may  now  extend  this  a  little.  Suppose  that 
we  have  two  isomeric  substances,  each  capable  of  taking  up 
four  bromine  atoms,  are  these  two  bodies  equally  saturated  or 
are  they  not  ?  The  question  of  unsaturation  thus  resolves  itself 
into  one  of  stability.  We  cannot  distinguish  between  the  bodies 
by  the  amount  of  bromine  they  take  up,  so  we  seek  some  other 
criterion.  Now,  in  the  case  of  two  substances,  one  of  which 
has  a  pair  of  conjugated  double  bonds,  while  in  the  other  the 
bonds  are  not  so  related,  the  second  substance  takes  up  the  four 
bromine  atoms  at  once,  but  the  first  one  takes  them  up  two 
by  two.  The  action  is  thus  more  precipitate  in  the  second 
instance,  and  we  should  be  tempted  to  consider  the  first  substance 
as  the  less  unsaturated  of  the  two.  In  fact,  as  Thiele  put  it, 
the  conjugated  double  bonds  partially  saturate  one  another. 


28o      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

Further,  when  an  unsaturated  acid  is  brought  into  conditions 
which  allow  it  to  undergo  isomeric  change,  it  is  almost  always 
converted  into  the  form  which  contains  the  ethylenic  bond  con- 
jugated with  that  of  the  carboxyl  group.  Evidently,  then,  this 
grouping  must  be  the  most  exothermic,  and  therefore  the  most 
saturated. 

We  may  now  sum  up,  as  far  as  possible,  the  various  points 
which  we  have  treated  in  the  foregoing  pages.  We  have  shown, 
in  the  first  place,  that  unsaturation  is  not  an  intrinsic  property 
of  any  molecule.  It  depends  largely  upon  the  nature  of  the 
outside  reagent ;  in  order  to  have  unsaturation  we  must  have 
two  substances,  each  specially  fitted  to  interact  with  the  other. 
In  fact,  the  addition  reactions  of  organic  chemistry  appear  to 
be  an  extreme  case  of  the  ordinary  reactions  of  salt  formation, 
such  as  takes  place  in  the  case  of  ammonia  and  acid.  Secondly, 
the  influence  of  the  other  (non-reacting)  parts  of  the  molecule 
may  play  a  very  considerable  part  in  any  addition  reaction,  so 
that  we  cannot  ascribe  the  same  meaning  to  every  double  bond 
that  we  write  down.  For  example,  the  ethylenic  bond  in 
maleic  acid  must  be  chemically  quite  different  from  that  in 
mesityl  oxide.  Thirdly,  just  as  unsaturation  can  be  influenced 
by  neighbouring  un saturations,  it  can  in  turn  exert  an  influence 
upon  groups  of  atoms  in  its  vicinity.  And,  finally,  if  we  have 
a  series  of  unsaturations  in  a  molecule  they  can  be  made  to 
rearrange  themselves  to  form  a  more  stable  system. 

It  has  thus  been  shown  that  the  term  "unsaturation" 
covers  a  very  wide  and  ill-defined  field.  Our  knowledge  of  the 
whole  problem  is  very  scanty  at  best,  and  we  are  handicapped 
(and  likely  to  remain  so)  owing  to  the  fact  that  no  one  has  the 
faintest  idea  of  what  really  lies  at  the  back  of  the  various 
phenomena  which  we  catalogue  under  this  name. 


CHAPTER   XIV 

CONCLUSION  * 

IT  often  happens  that  we  meet  with  a  series  of  apparently 
related  facts,  and  we  are  anxious  to  put  forward  some  plausible 
explanation  which  will  make  the  connection  between  them 
clear.  Under  these  conditions  we  may  proceed  on  either  of 
two  alternative  lines.  For  instance,  on  the  one  hand  we  may 
put  forward  some  general  idea  which,  without  troubling  about 
details,  will  allow  us  to  regard  the  matter  from  a  broad  point  of 
view ;  or,  on  the  other,  we  may  set  up  some  mechanical  model 
which  will,  as  far  as  possible,  reproduce  the  phenomena  we  set 
out  to  explain. 

At  the  first  glance,  the  former  method  seems  the  more 
likely  to  lead  near  the  truth ;  but  consideration  will  show  us 
that  this  is  not  the  case.  Suppose  that  our  general  idea  covers 
all  the  facts  known  at  a  given  time,  and  is  quite  comprehen- 
sible when  considered  in  relation  to  these  facts.  Then  let  us 
imagine  that  some  new  facts  are  discovered  which  do  not  quite 
agree  with  the  general  idea.  As  a  result,  the  general  idea  is 
widened  to  include  these  facts,  and  thus  it  becomes  more  vague 
than  it  was  before.  After  this  process  has  continued  for  a  time, 
the  general  idea  is  widened  insensibly,  until  it  ceases  to  have 
any  definite  meaning.  It  eventually  becomes  a  mere  rag-bag 
of  views  or  an  amorphous  mass  which  can  be  squeezed  to  fit 
any  vessel.  Naturally,  also,  it  has  ceased  to  have  any  value 
from  the  scientific  point  of  view — it  can  no  longer  stimulate 
us  in  research,  nor  can  it  aid  us  in  our  classification  of  facts. 

With  a  mechanical  hypothesis,  on  the  other  hand,  we  have 
something  definite,  which  either  does  or  does  not  fit  the  facts. 
If  it  fits  them,  well  and  good ;  but  as  soon  as  it  ceases  to  agree 

*  This  chapter  was  written  at  the  suggestion  of  Professor  Collie,  who  is 
partly  responsible  for  some  of  the  ideas  expressed  in  it. 


282      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

with  our  data  we  discover  the  inadequacy,  aud  can  discard  the 
mechanical  model,  replacing  it  by  another  which  is  more  in 
accord  with  our  increased  knowledge.  We  cannot,  as  in  the 
case  of  the  general  idea,  expand  it  and  make  it  more  vague,  but 
we  can  expand  it  while  retaining  its  definiteness. 

The  difference  between  the  two  methods  can  be  seen  by 
comparing  the  system  of  "  energetics  "  put  forward  by  Ostwald 
and  others  with  the  modern  structural  (mechanical)  theories 
of  organic  chemistry.  It  is  quite  certain  that  no  application 
of  the  purely  "  energetic "  view  to  organic  chemistry  could 
ever  have  carried  the  science  to  the  point  at  which  it  now 
stands. 

In  the  first  chapter  of  this  volume  the  question  of  the  real 
meaning  of  our  modern  structural  formulae  was  touched  upon, 
and  it  was  pointed  out  that  Kekule  and  Couper  differed  with 
regard  to  this  matter.  Up  to  the  present  time,  there  is  no 
doubt  that  the  Kekule  view  has  prevailed  to  a  great  extent. 
Our  formulae  for  organic  compounds  are  reaction-formulas ;  they 
represent  merely  the  behaviour  of  the  substance  when  treated 
with  various  reagents,  and  it  is  simply  on  this  account  that 
our  ordinary  structural  formulae  are  now  failing  to  meet  the 
demands  which  are  made  upon  them  by  recent  work.  If  we 
take  the  case  of  quinone  as  an  example,  we  find  that  its  formula 
is  written  in  either  of  two  ways — 

0 

II 

c  c o 

/  \  /  \ 

HC          CH  EC          CH 

II  II  II  | 

HC         CH  HC          CH 

\  /  \  /- 

C  C 

II 

o 


each  of  which  is  a  representation  of  its  method  of  reacting  with 
a  certain  reagent.  But  neither  of  these  formulae  allows  us  to 
foresee  the  fact  that  quinone  monoxime  will  react  as  if  it  were 
nitroso-phenol — 


CONCLUSION  283 

NOH  N:0 

11  I 

C  C 

X\  S\ 

HC         CH  HC         CH 

II  II  I  II 

HC         CH  HC         CH 

v     •       v 

II  I 

0  OH 

The  number  of  facts  of  this  type  which  have  accumulated  in 
recent  years  is  very  considerable,  and  the  result  of  this  increase 
in  knowledge  has  been  somewhat  remarkable.  Instead  of 
attempting  to  bring  their  formulae  into  harmony  with  the  facts, 
organic  chemists  have  been  content  to  drag  behind  them  a 
lengthening  chain  of  implications,  which  they  read  into  a 
formula;  e.g.  in  the  case  of  acetone  and  ethyl  acetate  we  do 
not  distinguish  in  our  formulae  between  the  two  carbonyl 
groups,  but  we  mentally  interpret  the  two  symbols  differently. 
Thus,  at  the  present  time,  it  is  quite  conceivable  that  a  student 
may  be  well  acquainted  with  the  meaning  of  all  the  ordinary 
chemical  symbols,  but  may  be  hopelessly  at  sea  with  regard 
to  the  behaviour  of  a  given  compound,  which  to  a  more  experi- 
enced chemist  is  implicitly  expressed  in  the  formula  which 
misleads  the  student. 

A  concrete  example  will  serve  to  bring  out  the  amount  of 
unexpressed  material  which  we  read  into  the  ordinary  formula. 
Let  us  consider  the  reactions  of  the  unsaturated  monobasic 
acids  in  presence  of  dilute  sulphuric  acid.  In  the  first  place, 
we  assume  that  an  addition  of  water  to  the  double  bond 
occurs — 

(CH3)2C  HO  (CH3)2C— OH       HO 


HC— CH2— CO  CH2— CH2— CO 

Now,  we  know  from  general  experience  that  when  one 
hydroxyl  group  lies  in  the  1,  6-position  to  another  in  the  same 
chain,  water  is  usually  eliminated  with  ease;  so  we  should 
deduce  that  the  next  step  in  the  process  would  be  such  an 
abstraction  of  a  water-molecule — 


284      RECENT  ADVANCES  IN  ORGANIC   CHEMISTRY 

(CH3)2C  -  OH      HO  (CH3)2C  --  0 

I  I         --  >  I  ! 

CH2-CH2—  CO  CH2  -  OH2—  CO 

The  formation  of  this  compound  is  actually  what  does  take 
place,  so  that  in  this  case  our  implications  are  justified;  but 
let  us  apply  the  same  series  of  ideas  to  another  instance.  Take 
the  case  of  vinyl-acetic  acid  (I.),  which  contains  the  double 
bond  in  exactly  the  same  position  as  in  the  other  substance. 
Applying  our  experience  as  before,  we  should  deduce  that  the 
final  product  on  heating  with  dilute  sulphuric  acid  would  be 
the  lactone  (II.).  In  practice  no  such  substance  is  formed,  the 
product  being  the  new  unsaturated  acid  (III.). 

CH2  ----  0 
CH2:CH.CH2.COOH    |  I  CH3  .  CH  :  CH  .  COOH 

CH2—  CH2—  CO 
(I.)  (II.)  (HI.) 

But  this  does  not  bring  us  to  the  end  of  the  possible  reac- 
tions of  this  class  of  substances,  for  if  we  take  the  case  in 
which  two  methyl  groups  are  attached  to  another  carbon  atom 
we  find  that  the  reaction  follows  yet  another  course  — 

CH2:CH.C(CH3)2.COOH 


CH3  .  CHOH  .  C(CH3)2  .  COOH 


CH3 .  CH  :  C(CH3)2  +  C02  +  H20 

Thus,  our  formulae  have  ceased  to  be  true  reaction  formulae, 
and  merely  serve  to  mislead  us  if  we  attempt  to  draw  any 
general  conclusions  from  them. 

But  this  by  no  means  ends  the  confusion  to  which  our 
modern  formulae  have  given  rise.  It  is  evident  that,  treated  as 
mere  reaction  formulae,  they  do  not  fulfil  our  requirements  ; 
but  there  is  another  side  to  the  question  upon  which  they  are 
quite  as  unsatisfactory.  Until,  say,  twenty  years  ago,  the 
relation  between  chemical  constitution  and  physical  properties 
had  not  been  very  thoroughly  investigated,  and  it  was  imma- 
terial whether  or  not  we  could  bring  the  two  sides  of  the 
subject  into  harmony  with  our  structural  formula?.  Now, 


CONCLUSION  285 

however,  that  is  all  changed.  The  study  of  the  physical 
properties  of  chemical  compounds  has  made  vast  strides,  even 
within  the  last  two  decades,  and  the  mass  of  material  now  at 
our  disposal  in  this  branch  of  the  subject  is  continually  increas- 
ing. At  the  same  time,  no  attempt  has  been  made  (except 
in  a  few  cases  like  Baeyer's  carbonium l  bond)  to  broaden  the 
basis  of  our  structural  formulae,  so  as  to  allow  us  to  merge  into 
them  both  the  physical  and  chemical  behaviour  of  substances. 
Instead,  we  have  the  usual  train  of  implications,  which  are  not 
expressed  in  the  formulae  we  write  down,  but  are  left  to  be 
inserted  mentally. 

Within  the  last  few  years,  also,  several  authors  have  pointed 
out  a  connection  between  the  reactivities  of  substances  and 
certain  of  their  physical  properties.  Such  a  relation  has  been 
shown  by  Bruhl  and  Schroder  in  the  case  of  refractive  index,2 
by  Kauffmann  3  in  that  of  magnetic  rotation,  and  by  Stewart 
and  Baly 4  in  absorption  spectra.  In  these  cases  we  are 
dealing  with  some  "  reaction-property,"  so  that  the  matter 
certainly  deserves  consideration  along  with  the  ordinary  chemical 
reactions. 

When  all  is  said  and  done,  however,  it  cannot  for  the  moment 
be  considered  desirable  that  we  should  get  rid  of  our  present 
style  of  formulae ;  they  represent  so  much,  and  are  undoubtedly 
more  convenient  than  any  substitute  at  present  conceivable. 
What  is  required  is  that  we  should  endeavour  to  bring  them 
into  harmony  with  reactions  on  the  one  side,  and  with  physical 
evidence  on  the  other.  If  this  could  be  done  we  should  see  our 
way  much  more  clearly  in  the  subject,  and  should  not  be 
misled  by  as  many  false  analogies  as  at  present  is  the  case. 

To-day  we  are  apparently  standing  on  the  verge  of  a  new 
view  of  things,  which  may  conceivably  carry  us  as  far  in 
advance  of  present-day  structural  chemistry  as  the  Couper  and 
Kekule  formulae  carried  the  chemistry  of  the  Type  Theory ;  and 
though  it  is  impossible  to  say  exactly  what  the  new  view  will 
be,  it  is  not  beyond  our  power  to  show  the  foundations  upon 
which  it  must  rest,  and  the  problems  which  it  must  solve  if  it 
is  to  constitute  a  real  advance  upon  our  present  position.  We 

1  Baeyer,  Ber.,  1905,  38,  569. 

2  Bruhl  and  Schroder,  Zeit.  physical.  Chem.,  1904,  50,  1 ;  1905,  51,  18,  513. 

3  Kauffmann,  ./.  pr.  Chem.,  1903,  II.  67,  334. 

4  Stewart  and  Baly,  Trans.  Chem.  Sue,,  1906,  89,  489. 


286      RECENT  ADVANCES   IN  ORGANIC   CHEMISTRY 

shall  endeavour  to  present  a  sketch  of  these  in  the  remainder  of 
this  chapter. 

It  will  be  remembered  that  the  chief  basis  upon  which  our 
modern  views  of  chemical  structure  were  laid  was  the  recogni- 
tion of  Frankland's  doctrine  that  atoms  had  a  constant  valency. 
For  many  years  this  view  sufficed  for  chemists,  but  in  the  more 
advanced  thought  of  the  present  day,  doubts  have  arisen  as  to 
its  truth  ;  and  it  seems  very  probable  that  in  a  few  years'  time  it 
will  cease  to  be  regarded  with  quite  the  same  definiteness  as  now. 
In  one  of  the  foregoing  chapters  it  was  pointed  out  that 
when  we  write  a  double  bond  between  two  atoms,  we  do  not 
always  mean  the  same  thing.  Thus  the  double  bonds  in  the 
cases  of  diphenyl-ethylene,  ethylene,  and  fulvene  certainly  do 
not  resemble  one  another  chemically;  in  the  first  case  the 
double  bond  is  not  attacked  by  bromine,  which  is  taken  up 
easily  by  the  double  bond  of  ethylene ;  but  while  the  fulvene 
series  are  oxidized  by  air,  ethylene  substances  are  not.  Thus 
we  have  an  increase  in  unsaturation  (or  reactivity  as  regards 
bromine  and  oxygen)  as  we  go  from  diphenyl-ethylene  through 
ethylene  to  the  fulvenes ;  while  we  symbolize  all  three  unions 
between  the  carbon  atoms  of  the  double  bonds  in  exactly  the 
same  way.  It  is  perfectly  evident  that  the  amount  of  reactivity 
is  different  in  these  three  cases,  and  therefore  the  "valency- 
force,"  which  gives  rise  to  reactions,  must  be  different  also. 

But  it  is  not  only  in  the  case  of  the  double  bond  that  we 
can  trace  this  alteration  in  value  of  valencies ;  we  can  discover 
it  in  the  case  of  single  bonds  as  well.  It  is  well  known  that  if 
we  take  bromo-benzene,  the  bromine  atom  is  held  to  the  carbon 
atom  of  the  nucleus  more  firmly  than  is  the  case  in  aliphatic 
bromine  derivatives.  But  if  we  nitrate  the  benzene  ring,  the 
bromine  in  the  aromatic  bromine  derivative  becomes  as  labile 
as  that  in  the  aliphatic  one.  This  increase  in  reactivity  can 
be  due  only  to  some  change  in  the  force  which  holds  together 
the  carbon  and  bromine  atoms ;  in  other  words,  the  "  valency- 
force  "  uniting  bromine  to  carbon  is  stronger  in  bromobenzene 
than  in  nitro-bromobenzene.1  Flurscheim2  has  carried  out 

1  When  the  above  paragraph  was  written  in  1908, 1  was  under  the  impression 
that  this  was  common  knowledge.     Dr.  Flurscheim  desires  me  to  mention,  how- 
ever, that  he  published  a  paper  on  the  point  in  1906  (Ber.,  39,  2016).— A. W.S. 

2  Flurscheim,  /.  pr.  Chem.,  II.  1902,  66,  329 ;  see  also  Werner,  Ber.,  1906, 
39,  1278. 


CONCLUSION  287 

some  experiments  by  means  of  which  he  shows  that  this 
variation  in  the  value  of  the  single  bond  is  quite  a  general 
property. 

It  may  be  supposed  by  some  that  if  we  accept  these  ideas 
we  shall  be  taking  a  retrograde  step,  and  plunging  ourselves  into 
a  web  of  inconsistencies  ;  but  surely  it  is  not  so !  At  the  time 
of  Frankland,  chemists  had  not  acquired  those  ideas  of  chemical 
structure  which  we  now  possess,  and  which  we  cannot  abandon 
without  having  something  better  to  take  their  place;  con- 
sequently, it  was  necessary  for  the  science  to  go  through  a  stage 
in  which  valency  was  regarded  as  a  fixed,  unalterable  force ; 
without  this  guiding  principle  the  work  of  the  last  forty  years 
would  have  been  impossible.  But  we  have  now  reached  a  stage 
when  we  can  look  back  and  enlarge  our  views  without  running 
the  risk  of  losing  hold  of  what  we  have  acquired.  Instead  of 
regarding  a  "  bond  "  as  a  fixed  unit,  we  can  afford  to  regard  it 
rather  as  the  sum  of  an  almost  infinite  number  of  small  forces  ; 
so  that  we  can  subtract  from  or  add  to  its  strength  within 
limits  without  bringing  it  out  of  the  category  of  a  "  bond  "  or 
valency.  For  example,  if  the  force  employed  in  uniting  two 
atoms  together  by  means  of  a  single  bond  be  termed  "  F3,"  then 
the  quantity  F  will  be  negligible  in  comparison  with  the  force 
of  the  single  bond.  But  it  is  quite  conceivable  that  this  small 
force  F  would  be  sufficient  to  cause  a  difference  of  reactivity 
according  as  it  were  added  to  or  subtracted  from  the  force  F2. 
Thus  the  two  forces  expressed  by — 

F2  +  F  and  F2  -  F 

would  not  differ  appreciably  in  their  capacity  for  uniting  two 
atoms,  and  certainly  would  not  be  so  different  as  to  allow  the 
first  atom  to  unite  with  two  others ;  yet  at  the  same  time  they 
would  be  sufficiently  different  to  produce  a  change  in  reactivity 
of  an  atom  attached  to  another  by  one  or  other  of  them. 

There  is  another  point  of  view  which  we  must  examine.  If 
we  are  going  to  broaden  the  basis  upon  which  our  chemistry 
rests,  we  must  be  prepared  to  include  the  physical1  as  well 
as  the  chemical  properties  of  substances  in  our  classification : 
and  naturally  for  an  explanation  of  the  physical  properties  of 

1  The  relations  between  chemical  constitution  and  physical  properties  have 
been  fully  dealt  with  by  Dr.  Smiles  in  his  book  on  this  subject.  Those  interested 
in  the  question  should  consult  especially  the  concluding  chapter  of  his  volume. 


288      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

substances  we  must  go  to  the  physicists,  and  from  them  we  can 
borrow  as  much  of  their  theory  as  seems  likely  to  help  us  in 
our  own  branch  of  science.  Within  the  last  few  years,  physics 
has  been  to  some  extent  rejuvenated  by  the  conception  of  the 
electron ;  and  it  may  not  be  amiss  to  give  a  brief  account  of  the 
modern  electrical  theory  of  matter  in  order  to  point  out  how 
it  might  be  applicable  to  our  own  subject.1 

According  to  the  modern  view  of  matter,  the  atom  consists 
of  a  "  positive  sphere  "  (i.e.  a  sphere  throughout  which  positive 
electricity  is  uniformly  distributed),  within  which  lie  a  number 
of  electrons.  Excluding  radio-active  bodies  from  our  considera- 
tion, it  may  be  said  that  the  electrons  in  an  atom  are  of  two 
kinds.  The  first  type,  "fixed  electrons,"  are  those  which 
remain  always  attached  to  the  positive  sphere  ;  the  other  class, 
"  detachable  electrons,"  are  more  or  less  free  to  wander  from 
atom  to  atom.  Now,  when  a  detachable  electron  leaves  one 
atom  and  makes  its  way  towards  another,  it  is  supposed  to 
carry  with  it  the  end  of  a  "tube  of  force,"  or  "Faraday  tube"  ; 
so  that  when  it  penetrates  into  the  second  atom,  and  remains 
there,  the  two  atoms  become  united  by  this  tube  of  force. 

It  is  evident  that  what  the  chemist  calls  valency,  the 
physicist  would  regard  as  an  accumulation  of  tubes  of  force. 
Thus  the  weakening  or  strengthening  of  a  bond  could  be 
regarded  either  as  a  reduction  or  increase  in  the  number  of 
Faraday  tubes  joining  two  atoms  together,  or  as  a  decrease  in 
the  strength  of  the  tube  of  force  uniting  the  one  atom  to  the 
other. 

Since  Faraday  tubes  are  supposed  to  be  mutually  repellent, 
this  hypothesis  furnishes  us  with  a  new  way  of  regarding 
Baeyer's  Strain  Theory.  It  is  obvious  that  in  a  double  bond 
between  carbon  atoms,  the  Faraday  tubes  will  be  more  numerous 
and  closely  packed  than  in  the  case  of  the  single  bond.  They 
will  thus  be  more  strongly  repelled  from  the  line  joining  the 
centres  of  the  two  carbon  atoms,  and  a  state  of  strain  will  be 
set  up  just  as  Baeyer  postulated.  The  same  holds  good  in  the 
case  of  the  acetylene  derivatives  also.2 

1  Nelson  and  Falk  (School  of  Mines  Quarterly,  1909,  30,  179)  have  developed 
this  line  of  thought  in  their  paper  on  "  The  Electron  Conception  of  Valency  in 
Organic  Chemistry,"  and  have  shown  how  isomerisrns  of  different  types  may  all 
be  expressed  in  terms  of  electronic  motion. 

2  Dr.  Fliirscheim  has  called  my  attention  to  a  paper  of  his  (J.  pr.  Chem.,  II. 


CONCLUSION  289 

On  the  physical  side,  it  has  been  shown  that  the  properties  of 
matter  are  very  largely  due  to  the  movements  of  the  electrons 
within  the  positive  sphere ;  while  on  the  chemical  side,  as  we 
have  seen,  the  reactivity  and  valency  of  atoms  depends  upon 
the  detachable  electrons  which  they  contain.  It  is  obvious 
that  these  two  phenomena  are  not  independent ;  but  that, 
on  the  contrary,  a  very  close  relationship  must  exist  between 
them.  Further,  physicists  have  shown  us  that  some  atoms  are 
capable  of  shedding  electrons  more  readily  than  others ;  which 
may  aid  us  in  our  correlation  of  physical  and  chemical 
properties. 

Thus  it  becomes  clear  that  any  future  advance  on  the 
theoretical  side  of  organic  chemistry  must  take  into  account 
the  following  branches  of  the  subject : — 

I.  The  arrangement  of  atoms  in  space. 

II.  The  mode  of  linkage  of  the  atoms  within  the  molecule. 

III.  The   influence  which   two   non-adjacent   atoms    in   a 

chain  can  exercise  upon  each  other. 

IV.  The  difference  between  ionic  and  non-ionic  reactions. 
Y.  Those  physical  properties  of  organic  compounds  which 

are  due  to  electronic  motions. 

1907,  76,  190)  in  which,  starting  from  somewhat  different  premises,  he  arrives  at 
similar  conclusions. 


BIBLIOGRAPHY 

WITHIN  the  last  decade  the  literature  of  organic  chemistry 
has  become  increased  and  specialized  to  a  much  greater  extent 
than  before,  and  it  may  be  useful  to  give  in  this  place  a  brief 
account  of  some  of  the  more  recent  works  in  various  branches 
of  the  subject. 

Beilstein's  "  Handbuch  der  Organischen  Chemie,"  which  is 
now  complete  in  nine  volumes,  is  too  well  known  to  need  any 
description ;  and  the  same  may  be  said  for  Kichter's  "  Lexikon 
der  Kohlenstoffverbindungen,"  to  which  three  supplements 
have  been  published.  The  former  work  was  completed  in 
October,  1906  ;  while  the  third  supplement  to  the  "  Lexikon  " 
is  complete  up  to  1904.  New  editions  of  both  works  are  in 
preparation. 

As  regards  practical  methods,  Lassar-Cohn's  "Arbeits- 
methoden  fur  organisch-chemische  Laboratorien "  has  now 
reached  its  fourth  edition  (1906-7),  which  exceeds  the  third 
edition  (1903)  by  no  fewer  than  607  pages.  The  index  of  the 
new  edition  is  much  superior  to  that  in  the  older  volume.  A 
new  work  on  somewhat  similar  lines :  "  Die  Methoden  der 
organischen  Chemie ;  ein  Handbuch  fur  die  Arbeiten  im  Labo- 
ratorium "  has  been  brought  out  by  Weyl.  The  first  volume 
and  part  of  the  second  have  been  published  (1909-10). 

The  historical  side  'of  the  subject  is  treated  by  Schorlemmer 
in  his  "  Kise  and  Development  of  Organic  Chemistry,"  but  this 
only  carries  the  matter  up  to  the  year  1894;  later  develop- 
ments are  to  be  found  in  Ladenburg's  "  Entwicklungsgeschichte 
der  Chemie"  (1907),  Meyer's  " Geschichte der  Chemie"  (1905), 
Armitage's  "History  of  Chemistry"  (1906),  or  Hilditch's 
"  Short  History  of  Chemistry  "  (1910).  The  history  of  modern 
theories  in  organic  chemistry  has  been  dealt  with  by  Pattison 
Muir  in  his  "History  of  Chemical  Theories  and  Laws,"  and 
also  by  Hilditch  in  his  "  Short  History."  The  Chemical 
Society's  "  Memorial  Lectures,"  as  well  as  the  obituary  notices 


BIBLIOGRAPHY  291 

in  the  Berichte  der  deutschen  chemischen  Gesellschaft  may  be 
consulted  by  those  who  are  interested  in  the  personal  side  of 
chemical  development. 

The  number  of  annual  summaries  of  work  published  con- 
tinues to  increase.  By  the  side  of  the  "  Jahresbericht  der 
Chernie "  and  Meyer's  "  Jahrbuch  der  Chemie,"  we  have  now 
the  Chemical  Society's  Annual  Eeports ;  while  a  "  Jahrbuch 
der  organischen  Chemie"  has  been  begun  by  J.  Schmidt 
(vol.  i.,  1907). 

Turning  to  the  modern  text-books  on  the  subject  of  organic 
chemistry,  the  most  important  is,  of  course,  Meyer  and  Jacobson's 
"  Lehrbuch  der  organischen  Chemie  "  (vol.  i.,  1893 ;  vol.  ii.  part 
1, 1902 ;  part  2,  1903).  It  is  unfortunate  that  this  work  is  not 
yet  complete,  the  volume  on  the  heterocyclic  substances  being 
still  lacking.  A  new  edition  of  the  first  volume  is  in  prepara- 
tion, part  of  it  (dealing  with  the  aliphatic  substances  and  their 
mono-derivatives)  having  already  appeared  (1907).  A  tenth 
edition  of  the  Kichter-Anschutz  "Organische  Chemie"  has 
appeared  (vol.  i.,  1903  ;  vol.  ii.,  1905),  and  the  first  volume  of 
the  eleventh  edition  was  published  in  1909.  The  German 
edition  of  Koscoe  and  Schorlemmer  was  completed  some  years 
ago.  Among  more  recent  works  J.  Schmidt's  "  Kurzes  Lehr- 
buch der  organischen  Chemie  "  deserves  special  mention. 

In  recent  years  several  volumes  of  essays  on  various 
branches  of  organic  chemistry  have  appeared.  Of  these,  Lach- 
man's  "  Spirit  of  Organic  Chemistry "  is  the  most  original. 
It  contains  an  historical  account  of  the  development  of  various 
outstanding  researches,  such  as  those  on  rosaniline  dyes,  the 
sugars,  maleic  and  fumaric  acids,  Perkin's  reaction  and  aceto- 
acetic  ester.  A  French  collection,  published  under  the  title 
"  Ke'cents  Progres  de  la  Chimie,"  has  reached  its  third  volume 
(vol.  i.,  1904 ;  vol.  ii.,  1906 ;  vol.  iii.,  1908),  and  contains  much 
that  is  of  interest  to  the  organic  chemist.  Cohen's  "  Organic 
Chemistry  for  Advanced  Students,"  and  Keane's  "  Modern 
Organic  Chemistry  "  (1907)  probably  should  also  be  included 
in  this  category.  In  his  "Neuere  Anschauungen  auf  dem 
Gebiete  der  organischen  Chemie"  (1908)  Henrich  has  dealt 
with  the  development  of  the  more  important  modern  theories. 

We  must  now  mention  some  monographs  on  special 
subjects,  Since  1896  a  collection  of  pamphlets  has  been 


292      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

issued  by  Ahrens  under  the  title  "  Sammlung  chemischer  und 
chemisch-technischer  Vortrage;  and  recently  a  somewhat 
analogous  series  has  appeared  under  the  name  "  Die  Wissen- 
schaft."  We  need  not  deal  with  these  in  detail  here,  as  we 
shall  have  occasion  later  to  mention  the  numbers  which 
specially  concern  us. 

Under  the  head  of  stereochemistry  we  find  that  in  the  last 
ten  or  fifteen  years  a  perfect  flood  of  text-books  and  pamphlets 
has  been  issued,  which  testifies  to  some  extent  to  the  interest 
taken  in  this  branch  of  chemistry.  The  most  complete  work  of 
reference  on  the  subject  is  Bischoff  and  Walden's  "  Handbuch 
der  Stereochemie  "  (1894),  with  its  two  supplementary  volumes, 
BischofFs  "  Materialen  der  Stereochemie  "  (1904).  In  these  are 
abstracts  of  practically  every  paper  that  has  been  published  on 
the  subject  up  to  1902,  the  abstracts  being  grouped  according 
to  the  year  of  publication,  and  very  well  indexed.  Werner's 
"Lehrbuch  der  Stereochemie"  (1904)  and  Stewart's  "Stereo- 
chemistry" (1907)  are  the  most  complete  text-books  on  the 
subject.  Smaller  works  are  Hantzsch's  "  Grundriss  der  Stereo- 
chemie "  (1904),  van't  HofF s  "  Lagerung  der  Atome  in  Eaume  " 
(1908),  Mamlock's  "Stereochemie"  (1908),  and  Wedekind's 
booklet,  "Stereochemie,"  in  the  Sammlung  Goschen  (1906). 
Landolt's  "  Optical  Kotating  Power  of  Organic  Substances " 
(1902)  deals  with  one  section  of  the  subject  in  great  detail. 
Among  the  numerous  pamphlets  we  need  only  mention  the 
following :  Wedekind  and  Frohlich,  "  Zur  Stereochemie  des 
fiinfwertigen  Stickstoffs"  (1907);  Meyerhoffer,  " Gleichgewichte 
der  Stereomeren "  (1906) ;  Jones,  "  Stereochemistry  of  Nitro- 
gen" (British  Association  Keport,  1904);  Ladenburg  "  Ueber 
Eacemie  "  (Ahrens  Sammlung,  1903) ;  Schmidt,  "  Einfluss  der 
Kernsubstitution  auf  die  Eeaktionsfahigkeit  aromatischer  Ver- 
bindungen"  (Ahrens  Sammlung,  1902);  Scholtz,  "Einfluss  der 
Eaumerfiillung  auf  den  Verlauf  chemischer  Eeaktionen  "  and 
"  Die  optisch-aktiven  Verbindungen  des  Schwefels,  Selens, 
Zinns,  Siliziums  und  Stickstoffs"  (Ahrens  Sammlung,  1898 
and  1907). 

Three  other  papers  in  the  Ahrens  Sammlung  deserve 
mention.  Marckwald,  in  one  of  them,  gives  a  sketch  of  the 
"  Benzoltheorie  "  to  1897  ;  while  a  second  is  devoted  by  Goose 
to  the  "Beziehung  der  Benzolderivate  zu  den  Verbindungen  der 


BIBLIOGRAPHY  293 

Fettreihe "  (1898).  W.  Wislicenus,  in  the  same  series,  gave  a 
pamphlet,  "  Ueber  Tautomerie  "  (1897) ;  while  the  same  subject 
is  treated  by  Lowry  in  the  British  Association  "Keport  on 
Dynamic  Isomerism"  (1904). 

The  literature  of  the  terpenes  is  an  ever-increasing  one. 
Heusler's  "Die  Terpene"  was  published  in  1896,  and  is  now, 
to  a  great  extent,  out  of  date,  as  is  also  Scholtz's  pamphlet,  "Die 
Terpene,"  in  the  Ahrens  Sammlung  (1896).  Gildemeister  and 
Hoffman's  "Ethereal  Oils"  (1900)  deals  only  with  the  occur- 
rence and  commercial  side  of  the  question,  and  does  not  trench 
upon  the  problem  of  terpene  constitutions.  In  Meldola's  work 
on  "  The  Chemical  Synthesis  of  Vital  Products  "  (1904),  the 
occurrence  and  syntheses  of  many  terpene  derivatives  are 
described.  A  very  complete  account  of  all  the  alicyclic  series 
is  given  by  Aschan  in  his  work,  "  Die  Chemie  der  alicyklischen 
Verbindungen  "  (1905),  while  the  terpenes  themselves  are  very 
fully  described  by  Semmler  in  his  work  on  "  Die  setherischen 
Oele"  (1906).  In  both  of  the  two  last  works  the  authors  have 
given  very  clear  and  complete  accounts  of  terpene  structures. 
The  chemistry  of  camphor  has  been  dealt  with  by  Lapworth  in 
the  1900  British  Association  Eeport  on  "  The  Constitution  of 
Camphor,"  and  by  Aschan  in  "Die  Konstitution  des  Kamphers" 
(1903),  which  was  afterwards  incorporated  in  his  "Chemie  der 
alicyklischen  Verbindungen."  Wallach  has  republished  his 
papers  on  the  terpenes  in  a  volume  "  Studien  ueber  die 
Terpene"  (1909);  and  a  condensed  description  of  this  class 
of  compounds  has  been  written  by  Barthelt  (1909). 

The  chemistry  of  the  alkaloids  has  not  produced  any  ex- 
tensive literature  apart  from  the  papers  in  the  journals.  The 
older  books,  such  as  Guareschi's  "  Die  Alkaloide,"  are  out  of 
date,  to  a  very  great  extent,  as  regards  the  constitutions  of  the 
alkaloids,  though  they  are  still  useful  as  far  as  descriptions 
of  physical  and  chemical  properties  are  concerned.  Scholtz's 
pamphlet  on  "  Die  kiinstliche  Auf bau  der  Alkaloide  "  (Ahrens 
Sammlung,  1897)  contains  a  good  account  of  the  state  of  the 
subject  at  that  period.  Later,  Pictet's  "  Vegetable  Alkaloids  " 
(1904)  brought  the  subject  more  up  to  date.  We  are  most  in- 
debted, however,  to  J.  Schmidt,  who  has  brought  out  from  time 
to  time  small  volumes  upon  the  state  of  alkaloid  chemistry. 
Three  of  these  have  already  been  published  :  "  Ueber  die 


294      RECENT  ADVANCES  IN  ORGANIC  CHEMISTRY 

Erforschung  der  Konstitution  wichtiger  Pflanzenalkaloide " 
(1900);  "Die  Alkaloidchemie  in  den  Jahren  1900-1904"; 
"Die  Alkaloidchemie  in  den  Jahren  1904-1907."  It  is 
probable  that  the  series  will  be  continued.  The  pharmaco- 
logical side  of  the  subject  is  dealt  with  by  Frankel  in  his 
"  Arzneimittel  Synthese"  (1906). 

With  regard  to  the  sugars,  Tollens'  "Kurzes  Handbuch 
der  Kohlenhydrate  "  (1895)  ;  Lippmann's  "  Chemie  der  Zucker- 
arten"  (1895);  or  Maquenne's  "  Les  sucres  et  principaux 
derives"  may  be  consulted.  Fischer's  papers  have  been  re- 
printed under  the  title  "  Untersuchungen  Uber  Kohlenhydrate 
undFermente"  (1909). 

Fischer  has  republished  his  papers  on  the  purines  under  the 
title,  "Untersuchungen  in  der  Puringruppe"  (1882-1906), 
and  those  on  the  polypeptides  in  a  volume  called  "  Die  Amino- 
sauren,  Polypeptide  und  Proteine"  (1906).  The  following 
works  have  appeared  dealing  with  the  problems  of  the  proteins 
and  albumins  :  Mann,  "  Chemistry  of  the  Proteids "  (1906) ; 
Schryver,  "Chemistry  of  the  Albumens"  (1906);  Schulz, 
"Allgemeine  Chemie  der  EiweissstofFe "  (Ahrens  Sammlung, 
1906).  A  new  series  of  monographs  on  biochemistry  has 
recently  been  issued  under  the  editorship  of  Plimmer  and 
Hopkins.  Up  to  the  present,  the  following  volumes  have 
been  published : — Bayliss,  "  The  Nature  of  Enzyme  Action ; " 
Plimmer,  "  The  Chemical  Constitution  of  the  Proteins ; " 
Schryver,  "  The  General  Character  of  the  Proteins ; "  Osborne, 
"The  Vegetable  Proteins;"  Armstrong,  "The  Simple  Carbo- 
hydrates and  the  Glucosides."  Other  volumes  are  announced 
dealing  with  "The  Development  of  Biological  Chemistry" 
(Hopkins) ;  "  The  Carbohydrates  and  Polysaccharides  "  (Ling) ; 
"The  Fats"  (Leathes);  "Colloids"  (Hardy);  and  "Alcoholic 
Fermentation  "  (Harden). 

The  diazo-compounds  have  been  described  by  Hantzsch  in 
his  pamphlet  "  Die  Diazoverbindungen  "  (Ahrens  Sammlung, 
1903) ;  by  Morgan  in  the  British  Association  Eeport  of  1902 
on  that  subject ;  and  lastly,  by  Cain  in  his  recent  volume 
"  The  Chemistry  of  the  Diazo-compounds  (1908). 

Organic  dyestuffs  have  been  dealt  with  by  Nietzki  in  his 
"  Chemie  der  organischen  Farbstoffe "  (1901),  and  later  in 
his  pamphlet  "Die  Entwicklungsgeschichte  der  kiinstlichen 


BIBLIOGRAPHY  295 

organischen  Farbstoffe"  (Ahrens  Sammlung,  1902).  Cain  and 
Thorpe  have  recently  brought  out  a  work  on  "  Synthetic  Dye- 
stuffs  and  Intermediate  Products  from  which  they  are  derived." 
A  small  but  comprehensive  volume  in  the  Sammlung  Gb'schen, 
Bucherer's  "Die  Teerfarbstoffe,"  gives  a  condensed  account  of 
these  substances.  The  constitutions  and  properties  of  the 
naturally  occurring  dyes  have  been  described  by  Kupe  in  his 
"Chemie  der  natiirlichen  Farbstofle"  (Vol.  I.,  1900;  Vol.  II., 
1909). 

The  Ahrens  Sammlung  contains  also  some  treatises  on  more 
or  less  isolated  questions  of  chemical  interest,  such  as  Hjelt, 
"  Ueber  die  Laktone  "  (1903) ;  Wedekind, "  Die  Santoningruppe  " 
(1903) ;  and  Schmidt,  "  Ueber  die  Pyrazolgruppe  "  (1899) ;  "  Die 
Halogenalkylate  und  quaternaren  Ammoniumbasen "  (1899) ; 
"  Die  Nitrosoverbindungen  "  (1903) ;  and  "  Ueber  Chinone  und 
chinoide  Verbindungen  "  (1906). 

The  relation  between  colour,  fluorescence,  and  chemical 
structure  has  been  dealt  with  by  Kauffmann  in  three  pamphlets 
belonging  to  the  same  series :  "  Ueber  den  Zusammenhang 
zwischen  Farbe  und  Konstitution  bei  chemischen  Verbin- 
dungen" (1904) ;  "  Die  Beziehungen  zwischen  Fluoreszenz  und 
chemischer  Konstitution"  (1906);  "Die  Auxochrome"  (1907)  ; 
but  for  a  full  account  of  these  and  allied  subjects,  Smiles' 
volume,  "  The  Eelations  between  Chemical  Constitution  and 
some  Physical  Properties  "  (1910)  should  be  consulted. 

Finally,  we  may  turn  to  those  works  in  which  the  reactions 
of  the  laboratory  are  classified  and  regarded  from  the  point  of 
view  of  their  value  in  synthetic  work.  Posner,  in  his  "  Synthe- 
tischen  Methoden  der  organischen  Chemie,"  has  inverted  the 
usual  order  of  text-books ;  for  instead  of  classifying  reactions 
according  to  the  compounds  which  they  produce,  he  classifies 
compounds  according  to  the  nature  of  the  reaction  which  gives 
rise  to  them.  Lassar  Cohn,  in  his  "  Allgemeine  Gesichtspunkte 
der  organischen  Chemie,"  has  collected  together  many  instances 
in  which  reactions  cannot  be  carried  through  conveniently  in 
the  ordinary  manner,  and  he  shows  how  by  resorting  to  various 
artifices  the  required  product  may  be  obtained.  The  Grignard 
reaction  and  its  various  applications  have  been  described  in  detail 
by  Schmidt  in  "  Die  organischen  Magnesium verbindungen  und 
ihre  Anwendung  zu  Synthesen  "  (Ahrens  Sammlung,  1905) ;  and 


296      RECENT  ADVANCES  IN   ORGANIC  CHEMISTRY 

by  McKenzie  in  the  1907  British  Association  Eeport  on  the 
subject.  The  whole  question  of  recent  synthetic  chemistry  has 
been  dealt  with  by  Schmidt  in  his  work,  "  Die  synthetisch- 
organische  Chemie  der  Neuzeit"  (Die  Wissenschaft,  1908). 

In  concluding  this  notice  of  the  current  literature  of  organic 
chemistry,  it  may  be  well  to  point  out  one  or  two  branches 
which  still  remain  unexhausted.  In  the  first  place,  there  is 
room  for  a  second  work  on  the  lines  of  Lachman's  "  Spirit  of 
Organic  Chemistry,"  as  a  perusal  of  that  volume  generally 
stimulates  in  the  reader  a  desire  for  further  essays  of  the  same 
type.  Secondly,  it  seems  possible  that  a  very  interesting 
account  of  modern  research  in  organic  chemistry  might  be 
written  by  taking  up  in  turn  the  chief  workers  of  the  last  two 
decades  and  showing  how  from  one  investigation  they  were  led 
to  another.  Of  course  the  Memorial  Lectures  of  the  Chemical 
Society  and  the  obituary  notices  of  the  deutschen  chemischen 
Gesellschaft  cover  some  of  this  ground ;  but  in  them  we  have 
no  account  of  many  of  the  most  important  researches  of  the 
last  ten  years,  owing  to  the  fact  that  the  investigators  are  still 
alive.  Then,  a  third  book  might  be  written  to  show  the 
connection  between  organic  chemistry  and  chemical  industries. 
To  a  great  extent,  the  specialization  in  pure  chemistry  on  the 
organic  side  at  the  present  day  is  caused  by  the  difficulty  which 
the  ordinary  chemist  encounters  when  he  endeavours  to  get 
into  touch  with  the  commercial  side  of  the  subject.  A  book 
which  would  bridge  this  gap  would  be  of  considerable  service. 
Finally,  one  may  suggest  that  a  most  useful  volume  might  be 
written  by  any  one  who  would  go  to  the  original  literature  and 
endeavour  to  deal  critically  with  the  constitutions  attributed  to 
the  commoner  classes  of  organic  substances.  In  comparing 
text-books  with  original  papers,  one  is  often  struck  by  the  way 
in  which  a  tentative  suggestion  put  forward  in  a  paper  becomes 
dogmatic  in  tone  when  transferred  to  a  text-book ;  and  any 
one  who  would  assess  for  us  the  value  of  the  actual  experi- 
mental evidence  in  favour  of,  say,  the  presence  of  a  carbonyl 
radicle  in  a  carboxyl  group,  would  be  doing  work  of  much 
interest  and  of  very  considerable  importance. 


INDEX   OF   NAMES 


ACH,  161,  166 
Ahrens,  161,  166 
Anschiitz,  14,  291 
Armitage,  290 
Armstrong,  294 
Arnold,  247 
Arth,  62 

Aschan,  34,  77,  293 
Athanasescu,  145 

Auwers,  207,  209,  211,  217,  218,   220, 
235 

BABO,  117 

Baeyer,  5,  10,  11,  12,  26,  28,  35,  36,  60, 

87,  88,  89 

Baly,  215,  265,  267,  285 
Bamberger,  201,  203,  205,  206,  209, 212, 

213,  216,  219,  220,  285,  288 
Bandow,  155 
Barbier,  97,  98,  99, 102 
Barthelt,  293 
Bauer,  261,  262 
Baumann,  211 
Bayliss,  294 
Becker,  148 
Beckett,  146,  155 
Beckmann,  62 
Behrend,  161 
Beilstein,  290 
Senary,  190 
Berkenheim,  63 
Berthelot,  33 
Bertrand,  247 
Bischoff,  13,  291 
Blaise,  44,  275,  276 
Blanc,  72,  76,  79 
Blangey,  206 
Bode,  132 

Borsum,  228,  230,  233,  235,  236 
Bouchardat,  93 

Bouveault,  84,  97,  98,  99,  101,  102 
Boyd,  251 
Brady,  213 
Bredt,  76,  80,  81,  260 
Brickner,  77 
Brown,  131 
Bruce,  27,  32,  34 
Briihl,  32,  284 


Bucherer,  295 
Buchner,  25 
Butlerow,  8 

CAIN,  294,  295 

Galdwell,  249 

Caro,  206 

Carroll,  161 

Chick,  187 

Claisen,  83 

Cohen,  244,  291 

Collie,  10,  38,  180,  190,  191,  192,  193, 

194,  195, 196,  197,  281 
Comstock,  135 

Cone,  226,  230,  233,  234,  235,  238 
Cooper,  247 
Cotton,  251 

Couper,  3,  17,  18,  282,  285 
Crafts,  179 
CrSpieux,  122 
Curtius,  25,  177 

DALTON,  16 
Dewar,  14 
Dobbie,  151 
Dodge,  93 
Drude,  15 

EDWARDS,  267 
Einhorn,  61,  127 
Elkeles,  55 
Erlenmeyer,  jun.,  247 
Euler,  91 

FALK,  288 

Faraday,  288 

Federer,  247 

Feist,  190 

Fenton,  241 

Finkelstein,  145 

Fischer,  13,  14,  111,  161,  162,  166,  169, 

170, 171,  172,  173,  175,  177,  243,  234, 

249,  294 
Fisher,  41 
Fittig,  21,  117,  119 
Fliirscheim,  286,  288 
Forster,  75,  267 
Foster,  146 


298 

Frankel,  294 
Frankforter,  157 
Frankland,  3,  286,  287 
Freer.  26 

Freund,  26,  148,  157,  160 
Fritsch,  159 
Friedel,  179 
Frohlich,  292 


GAMS,  142 

Gardner,  81 

Gtenequand,  121 

Gerhardt,  17 

Gerngross,  169 

Gildemeister,  55,  293 

Ginsberg,  84,  85 

Goeschen,  292,  295 

Goldschmiedt,  140 

Gomberg,  223,  224,  225,  226,  228,  229, 

230,  231,  233,  234,  235,  237,  238,  239, 

240 

Goose,  292 
Gourmand,  101 
Grtebe,  5 
Griess,  5 

Grignard,  24,  40,  41,  44,  52,  206,  215 
Guareschi,  111,  293 
Guye,  15 

HAAKH,  252 

Haller,  61,  75,  76,  77,  79 

Hantzsch,  10,  13,  119,  120,  292,  294 

Harden,  294 

Hardy,  294 

Harries,  69,  94,  102,  260,  275 

Hartley,  15 

Haworth,  28 

Hayakawa,  255 

Heintschel,  232,  236 

Henle,  252 

Henrich,  291 

Hentzschel,  21,  28 

Hermann,  10 

Herzig,  114 

Hesse,  61 

Heusler,  292 

Hilditch,  191,  290 

Himmelmann,  102 

Hinrichsen,  261 

Hirschberger,  243 

Hjelt,  295 

Hoff,  van't,  12,  15,  16,  292 

Hoffmann,  293 

Hofmann,  153 

Homfray,  193 

Hopkins,  294 

Horbaczewski,  161 

Huber,  121 

IGLAUEE,  128 
Ipatjeff,  34,  91,  97 


INDEX  OF  NAMES 


JABLONSKI,  275 

Jackson,  76 

Jacobson,  10,  230,  232,  233,  235,  236, 

291 

Jahns,  119,  120 
Johnson,  69 
Jones,  247,  292 
Jiinger,  63 

KACHLER,  78 

Kallen,  260 

Kametaka,  29 

Kauffmann,  285,  295 

Kay,  52 

Keane,  291 

Kehrmann,  215,  231 

Kekule,  3,  4,  5,  6,  8,  11,  12,  14,  15,  17, 

260,  282,  285 
Keller,  117 
Kerscnbaum,  102 
Kipping,  13,  24,  247,  251 
Kishner,  22 
Klages,  61,  63,  263 
Kleber,  32 
Klever,  186 
Komppa,  72 
Kondakow,  69 

Konigs,  134,  135,  136, 137, 138,  140, 169 
Koppe,  118 
Ko'rner,  5,  14 
Koster,  111 
Kotz,  91,  62 
Kriigel,  27 
Kriiger,  104 

LAAE,  8,  9,  10,  264 

Labbe,  95 

Lachman,  291,  296 

Ladenburg,  5,  6,  27,  115,  116,  119,  130, 

131,  290,  292 
Laiblin,  121 
Landolt,  292 
Lapworth,  80,  293 
Lassar-Cohn,  290,  295 
Lauder,  151 
Lawrence,  44 
Leathes,  294 
Le  Bel,  12,  13,  15,  16 
Lees,  34 
Lellmann,  275 
Lenton,  80 
Leser,  97 
Levallois,  84 
Ling,  294 
Lippmann,  294 
Loew,  241 
Lohse,  261 
Lowry,  293 
Luniak,  169 


INDEX  OF  NAMES 


299 


MALIN,  78 

Mamlosk,  292 

Mann,  294 

Maquenne,  294 

Marchlewski,  111 

Marckwald,  244,  249,  250,  292 

Markownikoff,  28,  29,  35,  59,  254 

Marsden,  267 

Marsh,  81 

Martine,  61 

Matthiessen,  146 

MoKenzie,  244,  245,  249,  250,  296 

Mehrlander,  62 

Meldola,  293 

Mencke,  76 

Meth,  250 

Meyer,  E.,  290 

Meyer,  H.,  114 

Meyer,  J.,  251 

Meyer,  R.,  291 

Meyer,  Victor,  6,  13,  291 

Meyerhoffer,  292 

Michael,  253,  255 

Miller,  137,  138 

Montgolfier,  77 

Morgan,  294 

Moser,  24,  262 

Miiller,  266 

Muir,  290 

Mumme,  255 

Myers,  196 

NEF,  261 
Nelson,  288 
Nencki,  111 
Neuberg,  247 
Neville,  13 
Nietzki,  294 
Norris,  231 

OPPEBMANN,  276 
Osborne,  294 
Ostromisslensky,  247 
Ostwald,  282 

PASTEUR,  1, 12,  246,  247,  248,  251 

Paternd,  12 

Paul,  250 

Peachey,  13 

Perkin,  Sir  W.  H.,  16,  119,  291 

Perkin,  W.  H.,  24,  26,  28,  34,  39,  41,52, 

57,  60,  72,  74,  80,  157 
Pictet,  111,  121,  122,  123,  142,  145,  293 
Pinner,  121 
Plimmer,  294 
Pope,  13,  247 
Posner,  276,  295 
Pummerer,  193,  197 

RAMSAY,  2, 19,  115 
Rayleigh,  19 


Remsen,  117, 119 
Reyher,  80 
Riban,  77 

Richter,  M.  M.,  290 
Richter,  V.,  14,  291 
Roberts,  271 
Robinson,  157,  230 
Rohde,  137 
Roosen,  161 
Roscoe,  291 
Rosenberg,  76 
Roser,  147,  157 
Rudolf,  212 
Riigheimer,  119,  130 
Rupe,  295 

SABATIEE,  22,  28,  30,  34 

Salway,  151 

Sanders,  231 

Schauwecker,  94 

Schindelmeister,  69 

Schmidlin,  238 

Schmidt,  42,  93,  94,  95,  99,   104,  291, 

292,  293,  295,  296 
Scholtz,  119,  246,  292,  293 
Schorlemmer,  290,  291 
Schotten,  211 
Schroder,  285 
Schryver,  294 
Schulz,  294 
Schulze,  169 
Schwarz,  61,  62 

Semmler,  69,  84,  90,  99, 102,  293 
Senderens,  22,  28,  30,  34 
Simonsen,  44 
Skraup,  136,  139 
Slawinski,  85 
Slimmer,  244 

Smiles,  13,  32,  37,  246,  287,  295 
Sobrero,  85 
Staudinger,  186,  187 
Stewart,  186,  194,  196,   215,  263,  265, 

267,  285 
Stohmann,  32 
Strecker,  171 
Sudborough,  271 

TATTEBSALL,  57 

Thiele,  16,  45,  51,  258,   259,  260,  268, 

274,  279 
Thomas,  271 
Thompson,  250 
Thorpe,  72,  74,  80,  295 
Tickle,  192 
Tiemann,  42,  93,  94,  95,  97,  98,  93,  100, 

101,  102,  104,  118 
Tigges,  99 
Tilden,  93 
Tinkler,  151 
ToUens,  294 
Tolloczko,  247 


INDEX   OF  NAMES 


Traube,  161,  162 

Tschitschibabin,  229,  230,  235,  236 
Tschugaeff,  90 

ULLMANN,  228,  230,  233,  235,  236 

VEEAGUTH,  29 

Verley,  97 

Vorlander,  255,  256,  257,  271,  276,  279 

WAGNEE,  41,  64,  77,  81,  85 

Walden,  225,  238,  292 

Walker,  131 

Wallach,  11,  42,  43,  50,  55,  66,  68,  76, 

82,  85,  293 

Wedekind,  E.,  246,  247,  251,  292,  295 
Wedekind,  0.,  246,  251 
Wegscheider,  118 
Weidel,  121 

Werner,  13,  16,  286,  292 
Weyl,  290 


Whitely,  244 

Wiederhold,  207 

Willstatter,  27,  29,  32, 34, 124, 127, 128, 

130,  132,  193,  197,  266 
Wilsmore,  186,  187,  188,  189 
Wislicenus,  J.,  12,  21,  28 
Wislicemis,  W.,  293 
Wohler,  147,  150 
Wolffenstein,  155 
Wren,  245 
Wright,  146, 155 
Wurtz,  21 

YATES,  34 
Young,  28 

ZALESKI,  111 

Zeisel,  113,  114 

Zeitschel,  102,  107 

Zelinsky,  24,  30,  52 

Zincke,  202,  203,  204,  207,  216,  218,  229 


INDEX 


SUBJECTS 

ABSOEPTION  spectra,  15,  265,  266,  271,  285 
Acetalamine,  159 
Acetaldehyde,  118 
Acetamide,  187 
Acetanilide,  187 

Acetic  acid,  115, 180,  186,  187,  197 
Acetic  anhydrides,  186,  191 
Acetic  ester.     See  Ethylacetate 
Acetoacetic  acid,  180,  186,  197 
„          anilide,  187 

ester,  9,  80,  189,  197,  222,  260,  263,  266,  278 
,,  ,,    structure  of,  9 

,,  ,,    condensation  in  ring  syntheses,  25,  26,  61 

Acetobutyl  hydrazone-hydrazide,  187 

,,          iodide,  24 
Acetone,  115,  187, 197,  263 
,,        dicarboxylic  ester,  263 
„        relations  to  keten  group,  197 
Acetonyl -acetone,  263 
Acetophenone,  130,  132 
Acetophenone  chloride,  130 
Acetoveratrone,  143 
Acetylacetone,  97,  197,  263 

,,  from  keten,  197 

Acetyladipic  ester,  44 
Acetylation  of  quinoles,  217,  220 
Acetyl  chloride,  132,  143,  187,  197,  211 
Acetyl  bromide,  211 
Acetylene,  116,  132,  270 

„         compounds,  270 
Acetylglutaric  ester,  44 
Acetylketen.     See  Diketen 
Acetylsuccinic  ester,  44 
Acidic  hydrogen  and  unsaturation,  278 
Acrylic  acid,  261 
Active  solvent,  action  of,  247 
Addition  reactions,  253  ff. 

,,  „         definition  of,  253 

„  „         degrees  in,  263 

Adipic  ester,  25 
Affinity  rearrangement,  264  ff. 
Alanine,  171 

,,       leucine,  171 
Albumins,  169,  170, 176 

„         hydrolysis  of,  170 
„         properties  of,  169,  176 
Albumoses,  170 


302  INDEX  OF  SUBJECTS 

Alkaloid  constitutions,  113  ft. 

„  „  methods  of  determining,  113 

Alkaloids,  14,  110  ff. 

,,         classes  of,  112 
,,         decompositions  of,  113 
„         definition  of,  110 
„         extraction  of,  112 

general  properties  of,  112 
isoquinoline  group  of,  140  ff. 
morpholine  or  phenanthrene  group  of,  112 
occurrence  of,  111 
practical  value  of,  110 
production  of,  in  nature,  111 
purine  group  of,  161  ff . 
pyridine  group  of,  115  ff. 
pyrrolidine  group  of,  120  ff. 
,,         quinoline  group  of,  134  ff. 
,,         synthesis,  115  ff. 

„  „         examples  of  complete,  115  ff.,  131 

Allantoin,  165 
Alloxan,  164 
Allyl  alcohol,  115 
,,    bromide,  115 
„    methyl  ketone,  273 
Aluminium  amalgam,  245 
„          chloride,  178 
Amido-acids  from  proteins,  170 
„          resolution  of,  171 
Amidomalonyl  urea,  162 
Amidopyridine,  122 
Amido-tetramethylene,  28 

„    -uracil,  163 

Amino-aceto-veratrone,  142,  143 
Ammonia's  action  on  unsaturated  ketones,  275  ff. 
Amyl  nitrite,  143 
Anhydrocamphoronic  acid,  80 
Aniline,  82, 187 
Apocamphoric  acid,  81,  82,  83 
Apophyllenic  acid,  149,  150 
Arabite,  248 

Aromatic  compounds,  Kekule's  views  on,  3 
Artificial  camphor,  87 
Asymmetric  amide  formation,  250 
„  carbon  atom,  12,  15 

esterification,  249 
hydrolysis,  249 
syntheses,  108,  241  ff. 

„        definition  of,  243 

„        failure  of,  in  cases  of  nitrogen  and  sulphur,  246 
Atrolactinic  ethyl  ether  nitrile,  130 
Atropic  acid,  130 
Atropine,  111,  131 

,,        constitution,  131 
„        synthesis,  131 
Azo-compounds  from  quinoles,  220 

BACTERIUM  xylinum,  247 
Baeyer's  Strain  Theory,  35,  288 
Barbituric  acid,  162 
Baumann-Schotten  reaction,  211 
Benzaldehyde,  130,  146,  251 


INDEX  OF  SUBJECTS  303 

Benzene,  3,  4,  5,  6,  7,  8,  9,  10, 11, 14,  28, 132, 180,  193, 194,  260 
,,        addition  of  bromine  to,  271 
,,        Baeyer's  researches  on,  10 

„        derivative  from  diacetylacetone,  183,  184, 186,  196 
„        formulae,  6  ff. 
,,        Kekule  on,  3 
,,       orientation  of  substituents,  4 
„        Thiele's  formula  for,  260 
Benzenoid  and  quinonoid  character,  215,  217 
Benzoic  acid,  13,  146 
Benzoin,  251 

Benzoylformic  acid,  asymmetric  synthesis  of  mandelic  acid  from,  245,  251 
Benzpyrene  compound,  198 
Benzyl  alcohol,  146 
Benzyl-hydrocotarnine,  154 
Bertrand's  method,  247 
Bibliography,  290  ff. 
Biochemical  methods  of  resolution,  247 
Bishydroxymethylene-acetone  derivatives,  197,  199 
Biuret  reaction,  176 

Boiling-points  of  paraffins,  defines,  and  polymethylenes,  31 
Bonds,  conjugated  double,  259 
Bonds,  variation  in  strength  of,  287 
Books,  annual  summaries,  291 

monographs,  291,  292,  294,  295 
of  essays,  291 
on  alkaloids,  293 
,  biochemistry,  294 
,  diazo  compounds,  294 
,  dyestuffs,  294 
,  history,  290 
,  practical  details,  290 
,  purines,  294 
,  reactions,  295 

,  relations  between  constitution  and  physical  properties,  295 
,  stereochemistry,  291 
,  sugars,  294 

,  synthetic  chemistry,  295 
,  terpenes,  293 
reference,  290 
some  suggested,  296 
text-books,  291 
Borneol,  76  ff. 

,,       constitution  of,  76 
„       in  asymmetric  syntheses,  246 
Bornyl  bromide,  77 
,,       chloride,  77 
„       iodide,  77,  89 
Bornylene,  77,  89 

,,          constitution  of,  89 
Bromacetic  ester,  80 
Bromacetylbromide,  186,  187 
Bromacrylic  acids,  261 

Bromine,  125,  125,  187,  207,  257,  261,  262,  269,  271,  286 
,,        addition  reactions,  33,  261  ff. 
,,        atom,  its  effect  on  additive  power,  261 
Bromoacetoacetic  ester,  187 
Bromoacetoacelyl  bromide,  188 
Bromoanhydrocamphoronic  chlorides,  81 
Bromocampholic  acid,  79 
Bromocamphoric  acid,  74 


304  INDEX   OF  SUBJECTS 

Bromooamphoric  anhydride,  80 
Bromohexahydrotoluic  acid,  57 
Bromoisobutyric  ester,  66,  80 
Bromo-isocaproyl-diglycylglycine,  175,  176 
Bromomaleic  acid,  262 
Bromomesaconic  acid,  262 
Bromostilbene,  262 
Bromotropane,  127,  130 

„  methyl  ammonium  bromide,  126 

Bromotropidine  hydrobromide,  127 
Brucine,  244 
Butane,  81,  32 
Butylene,  31,  32 
Butyraldehyde,  189 

CAFFEINE,  166, 168 

„          synthesis,  166 

Calcium  salt  method  of  preparing  polymethylenes,  21 
Camphane,  constitution  of,  76  ft. 
Camphanic  acid,  79,  80 

,,  ,,      synthesis  of,  80 

Camphene,  72,  76  ff.,  81,  85 
Camphlene  glycol,  81 
Camphoic  acid,  constitution  of,  81 
Campholic  acid,  78 
Campholide,  75,  79 
Camphor,  11,  72,  75,  76,  78,  83,  109 

artificial,  87 

„         as  active  solvent,  251 
,,         synthesis  of,  75  ff. 
Camphoranic  acid,  81 
Camphoric  acid,  11,  72,  74,  75,  79,  83,  89 

„  „     racemization  phenomena  of,  74 

„  „      synthesis  of,  72  ff. 

„         acids  as  asymmetric  hydrolyzing  agents,  249 
Camphoric  anhydride,  74,  75 

„  „          action  with  aluminum  chloride,  34 

Camphoronic  acid,  79,  80,  81 

„  „    constitution  of,  80 

,,  ,,    synthesis  of,  80 

Camphor  quinone,  268 

Camphorsulphonic  acids  as  asymmetric  hydrolyzing  agents,  249 
Cane-sugar,  attempted  asymmetric  hydrolyses  of,  249 
Carbethoxy-glycylglycyl-leucine  ester,  173 
Carbocinchomeronic  acid,  141 
Carbohydrates,  169 
Carbon  atom,  asymmetric,  12 

„       dioxide,  reduction  to  formaldehyde,  241 
„       disulphide,  115-224 
„       oxysulphide,  90 
,,       tetrachloride,  115 
Carbonium  bond,  285 
Caro's  reagent,  206 
Carone,  59,  60 

„       oxime,  60 
Caronic  acid,  59 
Carvenone,  109 
Carvestrene,  56  ff . 
Carvomenthol,  70 
Carvone,  47,  58,  69,  70 
„         hydrobromide,  69 


INDEX  OF  SUBJECTS  305 

Carvoxime,  46 

Carylamine,  60 

Gatechol,  202 

Chloracetal,  159 

Chloracetyl  chloride,  174 

Chlorine,  its  action  on  hexamethylene,  34 

„  ,,  phenols,  202 

Ghloro-carbonic  ester,  173 
Chlorocymene,  63 
Chloroform,  112,  224,  225 
Chloro-formic  ester,  164 
Chlorophyll,  111 
Chlorotheobromine,  166 
Chlorotheophylline,  165 
Chromic  acid,  115,  121,  134,  135,  139,  202 
Cinchene,  135 
Cincholoiponic  acid,  136 
Cinchonic  acid,  134,  139 
Cinchonidine,  140 
Cinchonine,  134,  135,  139,  140 

constitution,  134  ff. 
„  "  second  half  "  of,  134  ff . 

Cinchotenine,  135 
Cinchotoxine,  138 
Cineol,  52  ff.,  85 

„      oxidation  products  of,  55 
Cineolic  acid,  55,  56 

„        anhydride,  56 
Cinnamenyl-cyanacrylic  ester,  261 
Cinnamylidene-malonic  acid,  261 
Circularly  polarized  light,  251 
Cis-terpin,  53,  54,  55 

„         dehydration  products  of,  54 
„         dibromide,  53,  54,  55 
„         its  conversion  into  trans-terpin,  53 
Citral,  96, 100,  102  ff.,  106,  107 
„      group,  96  ff. 

,,      its  conversion  to  cyclocitral,  103,  104 
,»  ),  „        cymene,  102 

,,      stereoisomerism,  102,  107 
„      synthesis  of,  102 
Citronellal,  93,  94,  95,  96, 100,  101,  102 
„          dimethyl-acetal,  94 
,,          constitution  of,  93 
Citronella  oil,  93 
Citronellic  acid,  93,  100 
Citronellol,  93,  101 
Claisen's  reaction,  118 
Cocaine,  111,  133 

„        synthesis,  133 
Collie's  formula  for  benzene,  10 

,,  „        „    dehydracetic  acid,  189 

Complete  alkaloid  synthesis,  examples  of,  115,  131 
Conchinine,  140 

Condensation  methods  of  synthesizing  polymethylenes,  25,  26 
Conductivity,  electrical,  15,  225,  263,  271 
Coniine,  115  ff.,  125 

„      synthesis,  115  ff. 
Conjugated  double  bonds,  51,  259 
Constitution  and  reactivity,  261  ff. 

„  determination  in  alkaloid  series,  113  ff. 


306  INDEX   OF  SUBJECTS 

Constitution  determination  in  albumin  group,  170 
Cotarnic  acid,  147,  148 
Cotarnine,  147,  149,  150,  154,  160 

„          constitution,  147  ff. 

,,          solvents'  effects  on,  151 

,,          synthesis  of,  151  ff. 

„          tautomeric  forms  of,  150 
Cotarnolactone,  147,  149 
Cotarnomethine  methyl  iodide,  147,  149 
Cotarnone,  147,  149 
Couper's  formulae,  3 

„         views  on  formulae,  17,  282 
Cresol,  203,  207,  208 
Cresorcinol,  214 
Crotonic  acids,  6,  261 
Cryptogamia,  111 
Cyanacetic  acid,  163 

ester,  39,  104 
Cyanacetyl-urea,  163 
Cyanhydrin  reaction,  171,  243 
Cyanopentane  tricarboxylic  ester,  39 
Gyclobutene,  21,  28 
Cyclocitral,  103,  104 
Cyclogeranic  acid,  99 
Cycloheptadiene,  125 
Cycloheptatriene,  124,  125 
Cycloheptene,  124,  125 
Cyclohexanone  carboxylic  ester,  52 
Cyclo-octadienes,  30 
Cycloparaffins.     See  Polymethylenes 
Cyclopentadiene,  21 
Cyclopentanone,  21 
Cyclopropane,  21 
Cymene,  102, 103 

DBHYDBACETIC  acid,  180, 182, 186, 189, 190, 191 
,,  „         constitution  of  189  ff. 

isomer  of,  186,  191 

„  „         table  of  its  derivatives,  186 

Dehydration  reactions,  44,  50,  54,  64,  66 
Dehydrocamphoric  acid,  73,  74 
Desmotropic  bodies,  reactivity  of,  179 

„  „       magnetic  rotation  of,  15 

Desmotropy,  10 
Desoxymesityl  oxide,  273 
Diacetonamine,  273 
Diacetone  hydroxylamine,  67 
Diacetylacetone,  182,  183,  186,  195,  197 

„  derivatives.     See  Benzene,  Dimethylpyrone,  Isoquinoline, 

Lutidene,  and  Naphthalene 
,,  properties  of,  195 

Diacetyl-dimethylpyrone,  195 

,,        -hydroxy-benzyl-alcohol,  220 
Diacetylorcinol,  195 
Diacetylpentane,  24 
Diamidouracil,  164 

,,  ur  ethane,  164 

Diazo-compounds,  isomerism  of,  13 

,,  „  used  in  polymethylene  syntheses,  25 

Diazo-m ethane,  25 


INDEX  OF  SUBJECTS  307 


Dibenzal-tropinone,  130 

Dibromocotinine,  121,  122 

Dibromocrotonic  acid,  262 

Dibromofumaric  acid,  262 

Dibromohexamethylene,  28 

Dibromostilbene,  202 

Dibromoticonine,  121,  122 

Dichloropropylene,  27 

Dichlorotetrahydrocymene,  63 

Dielectric  constant  of  solvent  in  addition  reactions,  257 

Dihydrocarveol,  47,  70 

Dihydrocarvone,  58 

,-,  hydrobromide,  58 

Dihydronicotyrine,  123 
Dihydroxycamphoric  acid,  73 
Dihydroxydihydrocitronellal  acetal,  94 
Dihydroxylene,  98 
Dihydroxy-nonane,  24 
Dihydroxyphenyl-acetic  acid,  182 
Di-iodopurine,  167 
Di-isonitroso-tropinone,  130 
Di-isoprene,  93 

Diketen,  180, 186,  187,  189,  197 
„       properties  of,  187  ff.: 
„       refractivity  of,  188 
Diketides,  180, 189 
Diketoapocamphoric  acid,  82 
„  ester,  72 

Diketocamphoric  ester,  72 
Diketohexamethylene,  28 
Diketopiperazine,  175 
Dimethoxy-quinoline,  140 
Dimethyl-acrylic-acid,  261 
,,        allene,  92 
„        amine,  125 
,,        aminocycloheptadiene,  126 
,,        dihydroxy-heptamethylene,  24 
,,        fumaric  acid,  262 
,,        glutaric  ester,  72 
,,        granatanine,  29 
„        hydroxylamine,  206 
pentamethylene,  35 
homocatechol,  141,  142 
methylpyrrolidinium  iodide,  92 
methylpyrrolidine,  92 
pentamethylene,  35 
pyrone,  182,  186,  191,  192,  193,  194, 195,  196,  270 

constitution  of,  193 
,,        isomer,  194 
„        properties  of,  193 
„        salts,  192 
quinole,  206,  207 
sulphide,  270 

trimethylene  dicarboxylic  acid,  59 
urea,  165 

uric  acids,  165,  166 
Dinaphthol  derivative  of  diacetylacetone,  198 
Dipentene,  44  ff.,  50,  55,  93 

,,  action  of  nitrosyl  chloride  on,  45 

,,  constitution  of,  44  ff . 

„  hydrobromide,  53,  54,  55 


3o8  INDEX   OF  SUBJECTS 

Dipentene  nitrosochloride,  46 
Diphenyl-bromo-ethylene,  262 
»  ,,      propylene,  262 

ethylene,  262,  286 
,,        -methyl-propylene,  262 
„        propylene,  262 

Dissociation  constant  and  additive  power,  263 
Double  bonds,  action  of  nitrosyl  chloride  on,  45 
„       and  hydroxylamine,  67 
,,       and  niercaptans,  276 
„       conjugated,  51,  259 
„       their  behaviour  on  oxidation,  40 
salts,  270,  272 
Dynamic  and  static  views  of  chemistry,  16 
,,         views  of  addition  reactions,  263 

ECGONINE,  132,  133 

,,  constitution,  132  fi. 

„  synthesis,  132  ff. 

Electric  absorption,  15 
Electrical  conductivity,  15,  225,  263,  271 
Electric  discharge,  silent,  38 
Electrons,  288,  289 
Esterification;  selective  partial,  246 

,,  unsaturation's  influence  on,  271 

Ethane  tetracarboxylic  ester,  26,  27 
Ethereal  oils,  38,  91 
Ethyl  acetate,  152,  187,  189,  197 
Ethylene,  36,  39,  132,  269,  286 

Ethylenes  and  polymethylenes,  relative  degrees  of  unsaturation,  33 
Ethylidene-propionic  acid,  202 
Ethyl-sulphuric  acid,  132 
Exhaustive  methylation,  29 

FAEADAY  tube,  288 

Fats,  169 

Feist's  formula  for  dehydracetic  acid,  190 

Fenchane,  constitution  of,  84 

Fenchene,  82,  83,  85 

,,         constitution  of,  82  ff. 
Fenchocamphorone,  82,  83 
Fenchone,  82,  84 

,,          constitution  of,  82  fi. 
Fenchyl  alcohol,  82,  84 

„  „       constitution  of,  84 

„        chloride,  82 
Ferments,  170,  177 

Fischer's  methods  of  synthesizing  polypeptides,  172  ff. 
Fittig-Wiirtz  reaction,  preparation  of  polymethylenes  by,  21 
Formaldehyde,  111,  178,  241 

,,  conversion  of,  into  fructose,  141 

Formic  acid,  68 
Formulae,  views  of  Couper  and  Kekule  on,  17,  18 

„        implications  in  modern,  283 
Friedel-Crafts'  reaction,  132, 179 
Fructose  from  formaldehyde,  241 

„         syntheses  in  plants,  241 
Fulvene,  287 
Fumaric  acid,  262 

„  f      ester,  25 
Fungi,  resolution  of  racemates  by,  247 


INDEX   OF  SUBJECTS  3<>9 


GALLIC  acid,  147,  148 
Geranial,  107 
Geranic  acid,  96,  98  ff. 

„          ,,     synthesis  of,  98 
Geraniol,  96,  102,  106  ff. 
Glucose,  111,  251 
Glutaric  acid,  131 

,,  nitrile,  115 
Glycerine,  115,  131 
Glycine,  173, 174, 175 

,,       ester,  174 
Glycocoll,  173 
Glycyl,  173 

,,      chloride,  175 
Glycylglycine,  173,  174,  175 

,,  carboxylic  ester,  173 

ester,  173 

„  glycine,  175 

„  leucine,  173 

Glycylglycylglycylglycine  carbethoxy-ester,  173 
Glycylglycylleucine  carboxylic  ester,  173 
Gnoscopine  synthesis,  157 
Grignard  reaction  in  terpene  syntheses,  40,  41,  44,  52,  57 

„  „          „    quinole  syntheses,  206,  215 

Guye's  hypothesis,  15 


HAEMOGLOBIN,  111 

Hantzsch- Werner  theory,  13 

Heat  of  combustion  of  polymethylenes,  32 

,,      formation  of  trimethylene,  33 

„      bromine  addition  to      ,,      33 

„      sulphuric  acid      ,,        ,,      33 
Helicin,  244 
Hemipinic  acid,  147 
Hemiterpenes,  39 
Heptamethylene,  29,  31,  35,  36 

„  method  of  preparing,  29 

Heptane,  31,  32 
Heptene,  31,  32 

Herzig  and  Meyer's  method,  114 

Hexachloro-diketo-K-hexen,  202 

„          E-penten,  202 

„  „  -hydroxy-carboxylic  acid,  202 

Hexahydrocinchomeronic  acid,  136 
Hexahydrocymene,  39 
Hexahydro-hydroxy  benzoic  acid,  57 
Hexahydroxylylic  acid,  34 
Hexamethylene,  28,  31,  33,  34,  35,  36 

„  conversion  into  methyl-pentamethylene,  34 

„  methods  of  preparing,  28 

Hexane,  31,  32 
Hexaphenyl-ethane,  223 
Hexene,  31,  32 

Hindrances  to  reactions,  13,  261  ff . 
Hofmann's  reaction,  153 
Homocamphoric  acid,  76 
Homophthalic  acid,  76 
Homoprotocatechuic  acid,  143 
Homoterpenylic  acid,  synthesis  of,  44 

,,  „          methyl  ketone,  42 

Homoveratric  acid,  143 


3io  INDEX   OF  SUBJECTS 

Homoveratroyl  chloride,  143 

„  -amino-aoeto-veratrone,  144 

-hydroxy-homoveratrylamine,  144 
Hydrastine,  158, 159,  161 

,,  constitution,  160 

„  hydrochloride,  160 

„          synthesis,  158 

Hydrazone  formation  applied  to  resolution  of  racemates,  247 
Hydriodic  acid,  34,  35,  129,  255 

Hydrobromic  acid,  40,  53,  55,  57,  59,  69,  115,  125,  127,  209,  210,  211,  216,  262 
Hydrochloratropic  acid,  131 
Hydrochlorocarvoxime,  87 
Hydrocotarnine,  146, 155, 156 
,,  synthesis,  155 

Hydrogen  peroxide,  115 
Hydrohydrastinine,  159,  160 
Hydroquinone,  201 
Hydroxybenzoic  acid,  57 
Hydroxycamphoronic  acid,  81 
Hydroxydichloropurine,  167 
Hydroxydihydrogeranic  acid,  99 
Hydroxyfenchenic  acid,  82,  83 
Hydroxyhexahydrotoluic  acid,  lactone  of,  57 

ester,  40 
Hydroxylamine,  193,  212,  213,  275 

„  and  double  bonds,  67,  275 

Hydroxymenthylic  acid,  62,  65 
Hydroxytoluic  acid,  48 
Hydroxytrimethylglutaric  ester,  80 

IMPLICATIONS  in  modern  formulae,  283 
Indiarubber,  isoprene  produced  from,  92 
Influence  of  constitution  on  reactivity,  261  ff . 
Intramolecular  acetoacetic  ester  condensation,  25,  26,  61 

„  changes  in  quinoles,  215  ff. 

Iodine  bromide,  255 

„     chloride,  115,  255 
lodoacetic  ester,  98 
lodoheptamethylene,  35 
lodopropionic  ester,  39 
Ionic  hypothesis,  18 
lonone,  104,  105 
Irone,  106 
Isoborneol,  77 
Isocamphoric  acid,  75 
Isoconiine,  116 
Isocrotonic  acid,  261 

Isomeric  form  of  dimethyl-pyrone,  194.     See  also  Orcinol 
Isomyristicin,  151,  152 
Isophenylcrotonic  acids,  276 
Isoprene,  91,  92 

,,        polymerization  of,  92,  93 
„        syntheses  of,  91 
Isopropyl  alcohol,  115 
Isopulegol,  95 
Isoquinoline  alkaloids,  140  ff. 

„         derivative  of  diacetylacetone,  183,  185,  186,  196 

KEKULE'S  formulae,  3 

,,  vibration  hypothesis,  6  ff. 

„  views  on  formulae,  17,  282 

Keten,  179,  180,  186,  187,  189,  197 


INDEX  OF  SUBJECTS  31 1 

Keten  properties  of,  186 

„      table  of  its  derivatives,  186 
Ketobromides,  208 
"  Keto-enol "  type,  179 
Ketohexahydrobenzoic  acid,  39,  57 
Ketopentamethylene,  21,  22 

M  „  carboxylic  ester,  25 

Kishner's  method,  22 
Konigs'  cinchonine  formula,  138,  139 

„       loiponic  acid  formula,  137 

LAAR'S  hypothesis,  9,  264 
Labile  groupings  of  atoms,  8  ff. 
Lactic  acid,  245,  251 
„          ,,     asymmetric  syntheses  of,  245 
„     isomerism,  Wislicenus  on,  12 
Lactones,  formation  of,  283,  284 
Lsevulinic  acid,  97,  106 

ester,  263 

Laudanosine,  synthesis,  145 
Le  Bel-van't  Hoff  theory,  12 
Lepidine,  135,  136 
Leucine  ester,  173 
Leucyl-octaglycyl-glycine,  176 
Leucyl-triglycyl-leucyl-octaglycyl-glycine,  176 
Leucyl-triglycyl-leucyl-triglycyl-leucyl-octaglycylglycine,  176 

Limonenes,  45,  50 

„  constitution  of,  50 

Linalool,  96, 106,  107,  108 
Loiponic  acid,  136,  137 
Lutidone,  183, 186, 196 

MAGNESIUM  methyl  iodide,  207 
Magnetic  fields,  251 

„        rotatory  power,  15,  271,  285 
Maleic  acid,  262 
Malonic  acid,  121,  162 

„      ester  polymethylene  syntheses,  25,  26 
Malonylurea,  162 

Mandelic  acid,  asymmetric  esterification  of,  249 
„        ,,        ,,       synthesis  of,  245 

,,        amides,  250 

„        esters,  hydrolysis  of,  250 

„  ,,       selective  formation  of,  249 

Mannose  in  cyanhydrin  reaction,  243 
Markownikoff  Rule,  59,  255 
Meconine,  146, 156 
Menthene,  63  ft. 

„         tertiary,  70 
Menthenone,  69 
Menthol,  63  ff. 

„        in  asymmetric  syntheses,  244, 245 

„        in  selective  esterification  and  hydrolysis,  249 
Menthone,  61  ff. 

,,         decomposition  products  of,  62 
,,         from  rhodinal,  101 
Menthylamine,  250 
Menthyl  mesaconate,  244 
Mercaptans  and  double  bonds,  276 
Meroquinene,  134,  135,  136,  137,  139 
Mesaconic  acid,  244,  262 


312  INDEX  OF  SUBJECTS 

Mesaconic  menthyl  ester,  244 
Mesityl  oxide,  67,  273,  274,  275 

,,       oxime,  67 
Mesoxalic  acid,  164 
Mesoxalyl-urea,  164 
Methoxyl  groups,  estimation  of,  113 
Methyladipic  acid,  62,  65,  93 
Methylamine,  121 
Methylation,  exhaustive,  114 
Methylcyclohexanone,  66,  68 
Methyl  dibromobutane,  92,  97 
Methylenedihydroxy-isoquinoline,  159 
Methyl-ethyl-malonic  acid,  244 

„      granatanine,  29 

„      heptenone,  56,  96,  97,  98,  102,  106 

,,  ,,  constitution  of,  97 

,,  ,,  syntheses  of,  96  ff. 

„      hexamethylene,  35 

,,      imino  groups,  determination  of,  114 

,,      isopropyl-pimelic  acid,  61 

„      mercaptan,  90 

„      methoxy-hydrastinine,  160 

,,  „         methylenedioxy-benzyl-dihydro-isoquinoline,  154 

„  ,,         methylene-dioxy-phenylpropionic  acid,  151,  152 

„      methylene-gallic-carboxylic  acid.     See  Gallic  acid 

,,      pentamethylene,  24 

„      phenyl-glycollic  acid,  asymmetric  synthesis  of,  245 

„      pyrrolidine,  92 

„      quinole,  210,  214 

„      radicle,  its  effect  on  additive  power,  261 

„      stilbene,  262 

„       succinic  menthyl  ester,  244 

„      tetrahydropapaverine,  145 

„      tropane,  126 

,,      tropidine,  126 
Michael's  Distribution  Principle,  255 

„        theory,  253 
Miller  and  Rohde's  cinchonine  formula,  138,  139 

,,  ,,        loiponic  acid  formula,  137 

Modifications  of  Pasteur's  resolution  methods,  247 
Molecular  refraction  and  ring  formation,  32 

,,         volumes,  32 
Monobromacetic  ester,  80 
Monocotyledons,  111 
Monoketides,  180 
Morpholine  alkaloids,  112 
Mucic  acid,  122 
Myristicin,  151,  152 

„          aldehyde,  151,  152 

NAPHTHALENE  derivative  of  diacetylacetone,  183,  184, 186, 196 
Narceme  constitution,  157 
Narcotine,  146,  147,  156,  157,  158,  161 

„  constitution,  156,  157 

„  synthesis,  157 

Nef's  views,  261 
Neral,  107 

Nerol,  96,  102, 106  ff . 
Neutralization  of  affinity,  253 
Nicotine,  120  ff . 

„        constitution,  120  ff. 

„        synthesis,  122 


INDEX   OF  SUBJECTS  313 

Nicotinic  acid,  119,  120,  121 
Nicotyrine,  123 

„          synthesis,  123 

Nitration,  its  influence  on  addition  reactions,  262 
Nitrogen  compounds,  optically  active,  13 

,,        series,  attempts  at  asymmetric  synthesis  in,  246 
Nitromethane,  278 
Nitro-phenylhydrazine,  212 
Nitroso  and  iso-nitroso  derivatives,  45 
Nitrosyl  chloride,  45,  46,  48,  87 

„  „        action  of,  on  double  bonds,  45 

Nonane,  31,  32 
Nonomethylene,  30,  31,  32,  35,  36 

,,  preparation  of,  30 

Nonylene,  31,  32 
Normal  phellandrene,  69 

OCTADECAPEPTIDE,  175 

Octane,  31,  32 
Octene,  31,  32 
Octomethylene,  29,  30,  31,  35,  36 

„  method  of  preparing,  29  ff. 

Olefmes,  boiling-points  of,  31,  32 

„        molecular  volumes  of,  32 
Olefinic  terpenes,  38,  91  ff . 

,,  ,,        importance  of,  91 

"  Onium  "  salts,  272 
Opianic  acid,  146,  147,  156, 160 
OpticaUy  active  bodies,  12  ff. 

„  „  new  methods  of  producing,  246  ff. 

„  solvent,  247,  250 

Optical  rotatory  power,  15 
Orcinol,  182,  183,  186,  194,  196 
Orientation  in  benzene  series,  4 
Oscillation  hypothesis  of  Kekule,  6  ff. 
Oxalic  acid,  81,  106,  121,  162 

„     ester  condensation  applied  to  ring  syntheses,  25,  73 
Oxanthranol,  201 
Oxenes,  193 

Oximes,  isomerism  of,  13 
Oximidomalonylurea,  162 
Oximino-acids,  276 
Oxonic  acid,  165 
Oxonium  salts,  192,  193 
Oxygen,  quadrivalent,  192,  193 
Oxymethylene  derivatives,  formation  of,  83 

PAPAVBEINB,  140,  141,  142,  144,  145 

,,  constitution,  140  ff. 

,,  chloro-methyl  derivative  of,  145 

„  synthesis  of,  142  ff. 

Papaveroline,  140 
Paraffins,  boiling-points  of,  31,  32 

,,        molecular  volumes  of,  32 
Paraldehyde,  116 
Partial  valencies,  258 

definition  of,  258 

Pasteur's  methods  of  resolution,  246 
Pelletierin.     See  Pseudo-pelletierin 
Pentabromo-toluquinole,  208 
Pentaglycylglycine,  176 


3  [4  INDEX   OF  SUBJECTS 

Pentamethylene,  22,  28,  31,  32,  33,  34,  35,  36 

„    '          method  of  preparing,  22  . 
Pentamethylene  diamine,  115,  117 
Pentane,  31,  32 
Pentaphenyl-ethane,  230 
Pentene,  31,  32 
Peptones,  14, 170 

„        decomposition  products  of,  14,  170 
Perchlorethylene,  115 
Perchloro- vinyl-acetic  acid,  202 
Perkin's  reaction,  119 

Permanganate.     See  Potassium  permanganate 
Phellandrene,  68 

„  constitutions,  68  ff. 

Phenanthrene  alkaloids,  112 

Phenyl-acetyl-methoxy-methylenedioxy-phenyl-ethylamine,  153 
Phenylhydrazine,  14,  187,  190,  193,  212,  213,  220 
Phenyl-methyl-pyrazyl-phenyl-methyl-pyrazolone,  190 
Phenyl  radicle,  its  action  on  double  bonds,  262 
Phosphoric  acid,  135 
Phosphorus  pentabromide,  209,  210 

„          pentachloride,  135,  143,  174,  190,  230 
„          oxychloride,  163, 165,  166 

trichloride,  165,  167 
Phosphotungstic  acid,  176 
Phthalic  acid,  75 
Phthalide,  75,  76 
Physical  methods  in  organic  chemistry,  15,  18 

„       properties  and  chemical  constitution,  284 

„  „  and  reactivity,  285 

„  „  of  saturated  and  unsaturated  bodies,  76  ff.,  271 

Picoline,  116 
Pinacoline,  263 

Pinacone  formation  applied  to  polymethylene  syntheses,  24 
Pinene,  85,  87,  88,  89 

,,       constitution  of,  85  ff. 
„       hydrochloride,  87 
,,      nitrosochloride,  87 
Pinic  acid,  88 

„          constitution  of,  88 
Pinol,  85,  86,  87 

,,      constitution  of,  85  ff. 
Pinolglycol,  85 
Pinonic  acid,  88,  89 
Piperic  acid,  117,  118,  119 
Piperidine,  115,  117,  119 
Piperine,  117, 119 

„        constitution,  117  ff. 

„        synthesis,  117  ff. 
Piperonal,  117,  118,  159 
Piperonalacetalamine,  159 
Piperonylacrolein,  118 
Piperonylic  acid,  117,  118 
Piperyl  chloride,  119 
Plant  syntheses,  241,  252 
Plants  and  animals,  178 
Polarized  light,  absorption  of,  251 
Polyketides,  178  ff. 

,,         chief  properties  of  class,  200 
„         explanation  of  name,  180 
„         table  of,  197,  198 
Polymerization  of  ethylene,  38 


INDEX   OF  SUBJECTS  315 

Polymerization  of  keten,  179 
Polymethylenes,  20  ff.,  270 

and  ethylenes,  relative  degrees  of  unsaturation,  33,  272 
boiling-points  of,  31,  32 
,,  chemical  properties  of,  33 

heats  of  combustion  of,  32,  33 
,,  methods  of  synthesizing,  21  ff. 

,,  molecular  volumes  of,  32 

,,  nomenclatures  of,  20 

„  refractivities  of,  32 

,,  stabilities  of,  33 

Polypeptides,  169  ff. 

definition  of,  171 
,,  properties  of,  176 

Polypeptide  syntheses,  172  ff. 
Potassium  cyanate,  162 
,,          cyanide,  251 

permanganate,  oxidation  with,  33,  41,  42,  43,  55,  62,  64,  81,  82,  85, 

86,  94,  115,  117,  120,  135,  136,  141,  147,  151,  165,  272 
,,          sulphate,  dehydration  by,  44,  50,  57 
Potential  differences,  257 
Propane,  31 

Propenyl-methyl  ketone,  273 
,,  pyridine,  116 

Propylene,  27,  31,  33,  115,  255 

„  addition  of  hydriodic  acid  to,  255 

dichloride,  27,  115 
Proteins,  111,  170,  171 
Protocatechuic  acid,  117 

„          aldehyde,  118 
Pseudo-ionone,  104,  105 
„      narceine,  157 
„       orcinol,  186,  194 
„      pelletierin,  29 
Pseudo-pelletierin,  29 

phellandrene,  69 
tropine,  127,  128 

,,       its  conversion  into  tropine,  128,  129 
„       synthesis,  127,  128 
uric  acid,  162 
Pulegone,  67,  68,  94,  95,  96 

constitution  of,  67  ff. 
,,         decomposition  of,  68 
„         formation  of,  from  citronellal,  94,  95 
Purine  alkaloids,  111,  161  ff.,  179 
,,      derivation  of  name,  161 
„      group,  14 

,,  „      Fischer's  work  on,  14 

,,  ,,     nomenclature,  168,  169 

„      synthesis,  167 

Pyrazole  and  pyrazoline,  derivatives  in  polymethylene  syntheses,  25 
Pyridine,  14,  111,  115,  116,  117,  121,  123,  180,  182,  189,  193 
Pyridine  alkaloids,  115  ff. 
„         constitution,  14 
,,         Ladenburg's  synthesis  of,  115 
,,         occurrence  of,  in  alkaloids,  111 
,,         Bamsay's  synthesis  of,  115 
Pyridinium  methyl  iodide,  116 
Pyridylpyrrol,  122, 123 

Pyrones,  180,  182,  191,  192,  193,  194,  125,  196,  197,  200 
Pyrrol,  111 
Pyrrolidine  alkaloids,  112,  120  ff. 


316  INDEX   OF  SUBJECTS 

Pyruvic  acid,  asymmetric  synthesis  of  lactic  acid  from,  245 
„       ester,  265,  266 

QUATERNARY  ammonium  salts,  272 
Quinine,  139,  140 

„        constitution  of,  139  ff. 
Quinoles,  201  ff.,  235 

acetylation  of,  217 
constitution  of,  213  ff . 
definition  of,  201 
preparation  of,  205  ff. 
properties  of,  209  ff. 
„        rearrangements  of,  215  ff. 
Quinoline,  125 

„          alkaloids,  134 
"  Quinoline  half  "  of  cinchonine,  134 
Quinone,  201,  207,  215,  282 

,,        isomeric  forms  of,  266 
„        monoxime,  288 
Quinonoid  and  benzenoid  character,  215 

,,        nucleus,  effect  of  substitution  on,  215 

RACEMATES,  resolution  of,  246  ff. 
Racemization,  resolution  by,  250 
Reactive  and  non-reactive  bodies,  179 
Reactivity  of  ketones,  263 

„          variation  of,  287 

„          and  constitution,  261  ff. 

„          and  physical  properties,  285,  287 
Rearrangement  of  affinity,  265 
Refractive  index,  15,  32,  188,  193,  271,  285 
Resolution  by  amide  formation,  250 

„          ,,       differential  racemization,  250 
„          „       esterification,  249 
„          „       hydrolysis,  250 

Resolution  methods,  modifications  of  Pasteur's,  247 
Rhodinal,  96,  100,  101,  102 

„         production  of  menthone  from,  101 
Rhodinic  acid,  96,  100,  101 
Rhodinol,  96,  100,  101 
Ring  formation,  effects  of,  31  ff. 
Rosaniline,  226 
Rule,  Markownikofi,  59 

SABATIEB  and  Senderens'  reaction,  22,  28,  30,  34 

,,  „  „  „          applied  to  polymethylene  syntheses,  22 

Sandmeyer's  reaction,  226 
Sebacic  acid,  30 

"  Second  half"  of  cinchonine,  134,  135,  137,  138 
Selenium  compounds,  optically  active,  13 
Semicarbazide,  212,  213,  274 
Sesquiterpene  from  isoprene,  93 
Sesquiterpenes,  39 
Silent  electric  discharge,  38 
Silicon  compounds,  optically  active,  13 
Silver  oxide,  114 
Sobrerol,  85,  86,  87 
Sobrerythrite,  85,  86 
Soline,  111 

Solvent,  action  of  optically  active,  247,  260 
Sorbose  bacterium,  247 
Spacial  arrangement  of  atoms,  10,  11,  12  ff. 


INDEX  OF  SUBJECTS  317 

Spectra,  absorption,  15,  265 

Stability  of  polymethylenes,  33,  34 

Static  and  dynamic  views  of  addition  reactions,  263 

organic  chemistry,  10,  16 
Stereochemistry,  development  of,  12  ff. 
Stereoisomerism,  12  ff.,  272 
Steric  hindrance,  13 
Stewart's  theory,  263  ff. 
Stilbene,  262 
Strain  theory,  36,  288 
Strecker's  method,  171 
Styrolene  derivatives,  263 
Suberane,  29 
Suberic  acid,  29,  30,  124 
Suberone,  29,  124 
Suberyl  alcohol,  29,  124 

iodide,  29,  124,  125 

Substitution,  effect  of,  on  addition  reactions,  261  ff. 
Sugars,  relations  of,  to  keten  group,  197 
„       Fischer's  work  on,  13 

production  of,  from  formaldehyde,  178 
Sulphothiocarbonic  acid,  90 

Sulphur,  attempted  asymmetric  synthesis  of  quadrivalent,  246 
compounds,  optically  active,  13 

dioxide,  conductivity  of  triphenyl  methyl  salts  in,  225 
Sulphuric  acid,  heat  of  addition  to  trimethylene,  33 

„        dehydration  with,  50 
Sylvestrene,  60 
Synthetic  chemistry,  15 

TAETAEIC  acids,  asymmetric  synthesis  of,  246 
„      light  absorbed  by,  251 

Pasteur's  researches  on,  12,  246 
Tautomeric  bodies,  reactivity  of,  263 
Tautomerism,  9  ff. 
Terebic  acid,  43,  44 

„      synthesis  of,  44 
Terpenes,  11,  38  ff.,  179 

Baeyer  and  Wallach's  researches  on,  11 
classification  of,  38 
dicyclic,  72  ff. 

„        general  properties  of,  39 
,,        monocyclic,  38  ff. 
,,        nomenclature  of,  38 

olefinic,  91  ff. 
Terpenogens,  91 
Terpenylic  acid,  43,  85 

„  „    synthesis  of,  44 

Terpin,  52  ff. 

„      dibromide,  53,  54 
„      hydrate,  53 
Terpinene,  50  ff.,  55 

Terpineol,  39  ff.,  44,  49,  55,  57,  88,  89, 106,  108 
„         decomposition  of,  41  ff. 
„         dibromide,  85 
„         synthesis  of,  39  ff. 
Terpinolene,  50,  55 
Tetracarbonimide,  165 
Tetracetic  acid,  190,  191,  197 
Tetrabromo-cresol-tJ/-bromide,  208 

,,          ethyl-quinole,  216 
Tetrachlorocresol,  204 


3i8  INDEX  OF  SUBJECTS 

Tetrachloroquinone,  202 
Tetradecapeptide,  176 
Tetrahydrotoluic  acid,  40,  57 
Tetramethylene,  27,  28,  31,  33,  34,  35,  36 
„    '          preparation  of,  27 

carboxylic  acid,  27,  28- 
,,  amine,  28 

,,  -trimethyl-ammonium  hydroxide,  28 

Tetrapeptide  derivative,  173 
Tetraphenyl-ethane,  230 

ethylene,  262 
Theobromine,  166, 167 

„  synthesis,  166 

TheophyUine,  165,  166 

„  synthesis,  165 

Thermochemistry  of  the  polymethylenes,  32  fi. 
Thiele's  benzene  formula,  260 
„        theory,  51,  258,  268 
„  „        exceptions  to,  260,  261 

Thioacetic  anhydride,  187 
Thionyl  chloride,  173,  174 
Thujenes,  90 
Thujone,  90 

„        constitution  of,  90 
Thujyl  alcohol,  90 
Thymol  compound,  198 
Tiglic  acid,  261 

Tin  compounds,  optically  active,  13 
Toluidine,  203 
Tolyl-hydroxylamine,  205 
Transition  temperatures,  247 
Trans-terpin,  53, 54 
Triacetic  acid,  190,  191,  197 

„       lactone,  186, 190, 191 
Tribromacrylic  acid,  262 
Tribromotriphenyl  carbinol,  226 
-methyl,  227 

chloride,  226,  233 
Tribromoxylo-quinole,  201 
Trichloracetic  acid,  115 
Trichlorohydrin,  115 
Trichloropurine,  167 
Trigonelline,  119,  120 
Trihydroxyhexahydrocymene,  42,  43,  47 
Trimethylbromocyclopentane  carboxylic  ester,  74 
Trimethylacrylic  acid,  261 
Trimethylamine,  30,  92,  125,  147,  270     • 
Trimethylene,  21,  27,  31,  33,  35,  36 
,,  bromide,  115 

„  chloride,  27 

,,  preparation  of,  27 

Trimethylsuccinic  acid,  81 
Tripeptide,  175 

,,         derivative,  173 
Triphenyl-bromo-methane,  223 
carbinol,  229 

chloro-methane,  224,  230,  232 
methane,  230 
methyl,  222  ft. 

„         bromide,  225 

chloride,  224,  225 
„         double  compounds,  224 


INDEX   OF  SUBJECTS  319 


Triphenyl-methyl,  hexaphenyl-ethane  view  of,  228  ff. 
iodide,  224 

molecular  weight  of,  226,  229 
peroxide,  224,  229,  235 
preparation  of,  223 
properties  of,  223 
quinonoid  views  of,  231  fi. 
salts,  conductivity  of,  225 
tautomerism,  view  of,  237  ff. 
trivalent  carbon,  hypothesis  of,  225  ff . 
two  forms  of,  238 
Tropic  acid  synthesis,  130 
Tropidine,  124,  126,  127,  129 
„         methyl  bromide,  126 
,,         synthesis,  124  ff. 
Tropine,  127,  129, 131 

„       and  pseudotropine,  isomerism  of,  128 
„        synthesis,  127  ff. 
Tropinone,  29,  127,  128,  129,  130,  132 
„         carboxylic  acid,  132 

derivatives,  130,  132,  133 
„         sodium  salt,  132 
"  True  "  terpenes,  38 
Tube  of  force,  288 
Type  theory,  2,  3 


ULLMANN  and  Borsum's  hydrocarbon,  228,  239,  230,  235 

Umbelliferone  compound,  198 

Unsaturated  body,  definition  of,  269 

Unsaturated  ketones,  reactions  with  hydroxylamine,  67,  275  ff . 

Unsaturation,  269  ff. 

and  isomerism,  12 

degrees  of,  272 

its  chief  effects,  280 

variability  of,  279 


Uramil 


162 


Urea,  162, 163,  164 

Uric  aci£,  161,  162, 163,  164, 165, 167 
,,         constitution,  162 
„         decompositions,  164,  165 

salts,  163, 167 
,,         syntheses,  161  ff. 

Uroxanic  acid,  165 


VALENCY,  variability  of,  278  fi. 

Valerianic  acid,  asymmetric  synthesis  of,  244 

Vanillin,  143 

„       methyl  ether,  146 
Vestrylamine  hydrochloride,  60 
Vibration  hypothesis  of  benzene,  6  ff.,  10 

,,         intramolecular,  8 
Vinyl-acetic  acid,  284 
Violet  perfume,  artificial,  104 
Violuric  acid,  162 
Vorlander  Rule,  277  ff. 

„          theory,  255  ff.  - 

WANDERING  of  groups  in  quinoles,  215  ff. 


320  INDEX   OF  SUBJECTS 

XANTHINE,  168 
Xanthogenic  acid,  90 
Xylite,  248 
Xyloquinole,  212,  219 

ZEISEL'S  method,  113, 114 

Zincke's  researches  on  chlorination,  202  fi.,  207 


THE  END 


PKINTED   BY   WILLIAM   OLOWES   AND  SONS,   LIMITED,    LONDON   AND   BECCLES. 


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